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The mechanisms and roles of selective autophagy in mammals

Nature Reviews Molecular Cell Biology volume 24, pages 167–185 (2023)Cite this article

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Abstract

Autophagy is a process that targets various intracellular elements for degradation. Autophagy can be non-selective — associated with the indiscriminate engulfment of cytosolic components — occurring in response to nutrient starvation and is commonly referred to as bulk autophagy. By contrast, selective autophagy degrades specific targets, such as damaged organelles (mitophagy, lysophagy, ER-phagy, ribophagy), aggregated proteins (aggrephagy) or invading bacteria (xenophagy), thereby being importantly involved in cellular quality control. Hence, not surprisingly, aberrant selective autophagy has been associated with various human pathologies, prominently including neurodegeneration and infection. In recent years, considerable progress has been made in understanding mechanisms governing selective cargo engulfment in mammals, including the identification of ubiquitin-dependent selective autophagy receptors such as p62, NBR1, OPTN and NDP52, which can bind cargo and ubiquitin simultaneously to initiate pathways leading to autophagy initiation and membrane recruitment. This progress opens the prospects for enhancing selective autophagy pathways to boost cellular quality control capabilities and alleviate pathology.

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Fig. 1: Comparison of non-selective autophagy and selective autophagy.
Fig. 2: Receptor protein initiates de novo on damaged mitochondria.
Fig. 3: Mitophagy in health and disease.
Fig. 4: Schematic of lysophagy.
Fig. 5: Receptor recruitment during aggrephagy and xenophagy.

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References

  1. De Duve, C. & Wattiaux, R. Functions of lysosomes. Annu. Rev. Physiol. 28, 435–492 (1966).

    Article  PubMed  Google Scholar 

  2. Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Jiang, P. & Mizushima, N. Autophagy and human diseases. Cell Res. 24, 69–79 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Ohsumi, Y. Molecular mechanism of autophagy in yeast, Saccharomyces cerevisiae. Phil. Trans. R. Soc. Lond. B 354, 1577–1580 (1999).

    Article  CAS  Google Scholar 

  5. Hamasaki, M. et al. Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389–393 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Lamb, C. A., Yoshimori, T. & Tooze, S. A. The autophagosome: origins unknown, biogenesis complex. Nat. Rev. Mol. Cell Biol. 14, 759–774 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Gubas, A. & Dikic, I. A guide to the regulation of selective autophagy receptors. FEBS J. 289, 75–89 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. Johansen, T. & Lamark, T. Selective autophagy: ATG8 family proteins, LIR motifs and cargo receptors. J. Mol. Biol. 432, 80–103 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Kirkin, V. & Rogov, V. V. A diversity of selective autophagy receptors determines the specificity of the autophagy pathway. Mol. Cell 76, 268–285 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Nakagawa, I. et al. Autophagy defends cells against invading Group A Streptococcus. Science 306, 1037–1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Pan, J.-A. et al. TRIM21 ubiquitylates SQSTM1/p62 and suppresses protein sequestration to regulate redox homeostasis. Mol. Cell 61, 720–733 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee, Y. et al. Keap1/Cullin3 modulates p62/SQSTM1 activity via UBA domain ubiquitination. Cell Rep. 19, 188–202 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pickles, S., Vigié, P. & Youle, R. J. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr. Biol. 28, R170–R185 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tanaka, K. The PINK1-Parkin axis: an overview. Neurosci. Res. 159, 9–15 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008). The authors demonstrate the novel role of Parkin in mitophagy. Parkin is selectively recruited to damaged mitochondria and is critical for their autophagic degradation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jin, S. M. et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191, 933–942 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sekine, S. & Youle, R. J. PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC Biol. 16, 2 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yamano, K. & Youle, R. J. PINK1 is degraded through the N-end rule pathway. Autophagy 9, 1758–1769 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Deas, E. et al. PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum. Mol. Genet. 20, 867–879 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Kane, L. A. et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 205, 143–153 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Koyano, F. et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510, 162–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Shiba-Fukushima, K. et al. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 10, e1004861 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kazlauskaite, A. et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem. J. 460, 127–139 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Bingol, B. et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Kondapalli, C. et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2, 120080 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate parkin. PLoS Biol. 8, e1000298 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gladkova, C., Maslen, S. L., Skehel, J. M. & Komander, D. Mechanism of parkin activation by PINK1. Nature 559, 410–414 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sauvé, V. et al. Mechanism of parkin activation by phosphorylation. Nat. Struct. Mol. Biol. 25, 623–630 (2018).

    Article  PubMed  Google Scholar 

  29. Sarraf, S. A. et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496, 372–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ordureau, A. et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol. Cell 56, 360–375 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ordureau, A. et al. Dynamics of PARKIN-dependent mitochondrial ubiquitylation in induced neurons and model systems revealed by digital snapshot proteomics. Mol. Cell 70, 211–227.e8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tanaka, A. et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367–1380 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yamano, K., Fogel, A. I., Wang, C., van der Bliek, A. M. & Youle, R. J. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3, e01612 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yamano, K. et al. Endosomal Rab cycles regulate Parkin-mediated mitophagy. eLife 7, e31326 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Heo, J.-M. et al. RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway. Sci. Adv. 4, eaav0443 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Heo, J.-M., Ordureau, A., Paulo, J. A., Rinehart, J. & Harper, J. W. The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol. Cell 60, 7–20 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Moore, A. S. & Holzbaur, E. L. F. Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy. Proc. Natl Acad. Sci. USA 113, E3349–E3358 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Swatek, K. N. et al. Insights into ubiquitin chain architecture using Ub-clipping. Nature 572, 533–537 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Evans, C. S. & Holzbaur, E. L. Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons. eLife 9, e50260 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Burman, J. L. et al. Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J. Cell Biol. 216, 3231–3247 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Thurston, T. L. M., Ryzhakov, G., Bloor, S., von Muhlinen, N. & Randow, F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 10, 1215–1221 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Ravenhill, B. J. et al. The cargo receptor NDP52 initiates selective autophagy by recruiting the ULK complex to cytosol-invading bacteria. Mol. Cell 74, 320–329.e6 (2019). This study shows that FIP200, NDP52 and SINTBAD/NAP1 form a trimeric complex crucial for the initiation of xenophagy and that NDP52 directly recruits TBK1 and the ULK1 complex to invading bacteria.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Richter, B. et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc. Natl Acad. Sci. USA 113, 4039–4044 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vargas, J. N. S. et al. Spatiotemporal control of ULK1 activation by NDP52 and TBK1 during selective autophagy. Mol. Cell 74, 347–362.e6 (2019). This study shows that NDP52 binds to FIP200, which allows NDP52 to localize the ULK1 complex selectively to damaged mitochondria downstream of Parkin activation to initiate mitophagy. Additionally, this study shows that TBK1 activity fosters the association of NDP52 with the ULK1 complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Terešak, P. et al. Regulation of PRKN-independent mitophagy. Autophagy 18, 24–39 (2022).

    Article  PubMed  Google Scholar 

  48. Zhang, J. & Ney, P. A. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 16, 939–946 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Sandoval, H. et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 454, 232–235 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Novak, I. et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 11, 45–51 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Hanna, R. A. et al. Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J. Biol. Chem. 287, 19094–19104 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Princely Abudu, Y. et al. NIPSNAP1 and NIPSNAP2 act as ‘Eat Me’ signals for mitophagy. Dev. Cell 49, 509–525.e12 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Li, Y. et al. BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease. Cell Death Dis. 13, 14 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Nguyen, T. N. et al. Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation. J. Cell Biol. 215, 857–874 (2016). Using CRISPR-gene editing to knockout genes encoding the LC3/GABARAP family proteins, this work shows that these proteins are dispensable for autophagosome formation but are instead essential for the acidification of autophagosomes through their role in autophagosome–lysosome fusion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Itakura, E., Kishi-Itakura, C., Koyama-Honda, I. & Mizushima, N. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J. Cell Sci. 125, 1488–1499 (2012).

    CAS  PubMed  Google Scholar 

  56. Fu, T. et al. Structural and biochemical advances on the recruitment of the autophagy-initiating ULK and TBK1 complexes by autophagy receptor NDP52. Sci. Adv. 7, eabi6582 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shi, X. et al. ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer. J. Cell Biol. 219, e201911047 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yamano, K. et al. Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy. J. Cell Biol. 219, e201912144 (2020). This study reveals that the association between OPTN and ATG9A is important for mitophagy, suggesting that OPTN localizes ATG9A vesicles to provide membranes for mitophagy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. O’Loughlin, T. et al. OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion. J. Cell Sci. 133, jcs239822 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zachari, M. et al. Selective autophagy of mitochondria on a ubiquitin-endoplasmic-reticulum platform. Dev. Cell 50, 627–643.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Heo, J.-M. et al. Integrated proteogenetic analysis reveals the landscape of a mitochondrial-autophagosome synapse during PARK2-dependent mitophagy. Sci. Adv. 5, eaay4624 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bansal, M. et al. Optineurin promotes autophagosome formation by recruiting the autophagy-related Atg12-5-16L1 complex to phagophores containing the Wipi2 protein. J. Biol. Chem. 293, 132–147 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Chang, C. et al. Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy. Sci. Adv. 7, eabg4922 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shi, X., Chang, C., Yokom, A. L., Jensen, L. E. & Hurley, J. H. The autophagy adaptor ndp52 and the fip200 coiled-coil allosterically activate ulk1 complex membrane recruitment. eLife 9, e59099 (2020). Using in vitro reconstitution assays, this work shows that NDP52 binds to and allosterically stimulates the membrane-binding of FIP200 by inducing a dynamic conformation of the membrane-binding region of FIP200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kim, J., Kundu, M., Viollet, B. & Guan, K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Turco, E. et al. FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates. Mol. Cell 74, 330–346.e11 (2019). This study reports that p62 directly associates with the Claw domain of FIP200 to localize the ULK1 complex to ubiquitylated protein aggregates. Additionally, this study shows that the binding of p62 to FIP200 is mutually exclusive from the binding of p62 and LC3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Turco, E. et al. Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation. Nat. Commun. 12, 5212 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nguyen, T. N. et al. Unconventional initiation of PINK1/Parkin mitophagy by optineurin. Preprint at bioRxiv https://doi.org/10.1101/2022.08.14.503930 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Padman, B. S. et al. LC3/GABARAPs drive ubiquitin-independent recruitment of Optineurin and NDP52 to amplify mitophagy. Nat. Commun. 10, 408 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Valente, E. M. et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Clark, I. E. et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441, 1162–1166 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Park, J. et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157–1161 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Cai, X., Xu, H. & Chen, Z. J. Prion-like polymerization in immunity and inflammation. Cold Spring Harb. Perspect. Biol. 9, a023580 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Wang, C. & Youle, R. J. The role of mitochondria in apoptosis. Annu. Rev. Genet. 43, 95–118 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Johnson, B. N., Berger, A. K., Cortese, G. P. & Lavoie, M. J. The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax. Proc. Natl Acad. Sci. USA 109, 6283–6288 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bernardini, J. P. et al. Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy. EMBO J. 38, e99916 (2019).

    Article  PubMed  Google Scholar 

  78. Ham, S. J. et al. Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination. Proc. Natl Acad. Sci. USA 117, 4281–4291 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Youle, R. J. Mitochondria-Striking a balance between host and endosymbiont. Science 365, eaaw9855 (2019).

    Article  CAS  PubMed  Google Scholar 

  81. West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Wu, J. & Chen, Z. J. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 32, 461–488 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Moehlman, A. T. & Youle, R. J. Mitochondrial quality control and restraining innate immunity. Annu. Rev. Cell Dev. Biol. 36, 265–289 (2020).

    Article  CAS  PubMed  Google Scholar 

  85. Pickrell, A. M. & Youle, R. J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85, 257–273 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Borsche, M. et al. Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism. Brain 143, 3041–3051 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Surmeier, D. J. Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J. 285, 3657–3668 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Evans, C. S. & Holzbaur, E. L. F. Autophagy and mitophagy in ALS. Neurobiol. Dis. 122, 35–40 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Van Laar, V. S. & Berman, S. B. The interplay of neuronal mitochondrial dynamics and bioenergetics: implications for Parkinson’s disease. Neurobiol. Dis. 51, 43–55 (2013).

    Article  PubMed  Google Scholar 

  90. Aschrafi, A. et al. A heterogeneous population of nuclear-encoded mitochondrial mRNAs is present in the axons of primary sympathetic neurons. Mitochondrion 30, 18–23 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mandal, A. & Drerup, C. M. Axonal transport and mitochondrial function in neurons. Front. Cell Neurosci. 13, 373 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Coffey, J. W. & De Duve, C. Digestive activity of lysosomes. I. The digestion of proteins by extracts of rat liver lysosomes. J. Biol. Chem. 243, 3255–3263 (1968).

    Article  CAS  PubMed  Google Scholar 

  93. Boya, P. & Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434–6451 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Maejima, I. et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347 (2013). This paper shows that the clearance of damaged lysosomes occurs by autophagy and coined the term lysophagy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stahl-Meyer, J., Stahl-Meyer, K. & Jäättelä, M. Control of mitosis, inflammation, and cell motility by limited leakage of lysosomes. Curr. Opin. Cell Biol. 71, 29–37 (2021).

    Article  CAS  PubMed  Google Scholar 

  96. Hung, Y.-H., Chen, L. M.-W., Yang, J.-Y. & Yuan Yang, W. Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Nat. Commun. 4, 2111 (2013). This paper shows damaged lysosomes are ubiquitylated and that autophagic turnover is induced, termed lysophagy.

    Article  PubMed  Google Scholar 

  97. Aman, Y. et al. Autophagy in healthy aging and disease. Nat. Aging 1, 634–650 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Papadopoulos, C. et al. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J. 36, 135–150 (2017).

    Article  CAS  PubMed  Google Scholar 

  99. Eapen, V. V., Swarup, S., Hoyer, M. J., Paulo, J. A. & Harper, J. W. Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy. eLife 10, e72328 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Chauhan, S. et al. TRIMs and galectins globally cooperate and TRIM16 and Galectin-3 co-direct autophagy in endomembrane damage homeostasis. Dev. Cell 39, 13–27 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yoshida, Y. et al. Ubiquitination of exposed glycoproteins by SCFFBXO27 directs damaged lysosomes for autophagy. Proc. Natl Acad. Sci. USA 114, 8574–8579 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kravić, B. et al. Ubiquitin profiling of lysophagy identifies actin stabilizer CNN2 as a target of VCP/p97 and uncovers a link to HSPB1. Mol. Cell 82, 2633–2649.e7 (2022).

    Article  PubMed  Google Scholar 

  103. Koerver, L. et al. The ubiquitin-conjugating enzyme UBE2QL1 coordinates lysophagy in response to endolysosomal damage. EMBO Rep. 20, e48014 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang, L., Sheng, R. & Qin, Z. The lysosome and neurodegenerative diseases. Acta Biochim. Biophys. Sin. 41, 437–445 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Papadopoulos, C. & Meyer, H. Detection and clearance of damaged lysosomes by the endo-lysosomal damage response and lysophagy. Curr. Biol. 27, R1330–R1341 (2017).

    Article  CAS  PubMed  Google Scholar 

  106. McBrayer, M. & Nixon, R. A. Lysosome and calcium dysregulation in Alzheimer’s disease: partners in crime. Biochem. Soc. Trans. 41, 1495–1502 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lamark, T. & Johansen, T. Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int. J. Cell Biol. 2012, 736905 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Menzies, F. M., Fleming, A. & Rubinsztein, D. C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 16, 345–357 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Scotter, E. L. et al. Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species. J. Cell Sci. 127, 1263–1278 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Dikic, I. Proteasomal and autophagic degradation systems. Annu. Rev. Biochem. 86, 193–224 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Bjørkøy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005). This paper initially identifie the LIR domain and highlighted, for the first time, the role of p62 in aggrephagy.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Pankiv, S. et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131–24145 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Wurzer, B. et al. Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy. eLife 4, e08941 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Zaffagnini, G. et al. p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J. 37, e98308 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Clausen, T. H. et al. p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy. Autophagy 6, 330–344 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Liu, X. et al. The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy. J. Cell Biol. 216, 1301–1320 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Matsumoto, G., Shimogori, T., Hattori, N. & Nukina, N. TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation. Hum. Mol. Genet. 24, 4429–4442 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Savova, A., Romanov, J. & Martens, S. NBR1 directly promotes the formation of p62–ubiquitin condensates via its PB1 and UBA domains. Preprint at bioRxiv https://doi.org/10.1101/2020.09.18.303552 (2020).

    Article  Google Scholar 

  119. Sun, D., Wu, R., Li, P. & Yu, L. Phase separation in regulation of aggrephagy. J. Mol. Biol. 432, 160–169 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Sun, D., Wu, R., Zheng, J., Li, P. & Yu, L. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res. 28, 405–415 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kirkin, V. et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505–516 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Long, J. et al. Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-κB signalling. J. Mol. Biol. 396, 178–194 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Walinda, E. et al. Solution structure of the ubiquitin-associated (UBA) domain of human autophagy receptor NBR1 and its interaction with ubiquitin and polyubiquitin. J. Biol. Chem. 289, 13890–13902 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Agudo-Canalejo, J. et al. Wetting regulates autophagy of phase-separated compartments and the cytosol. Nature 591, 142–146 (2021).

    Article  CAS  PubMed  Google Scholar 

  125. Schultz, S. W. et al. Should I bend or should I grow: the mechanisms of droplet-mediated autophagosome formation. Autophagy 17, 1046–1048 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Sarraf, S. A. et al. Loss of TAX1BP1-directed autophagy results in protein aggregate accumulation in the brain. Mol. Cell 80, 779–795.e10 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ohnstad, A. E. et al. Receptor-mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy. EMBO J. 39, e104948 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lu, K., Psakhye, I. & Jentsch, S. Autophagic clearance of PolyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family. Cell 158, 549–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Ryan, T. A. et al. Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles. EMBO J. 39, e102539 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zellner, S., Schifferer, M. & Behrends, C. Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling. Mol. Cell 81, 1337–1354.e8 (2021).

    Article  CAS  PubMed  Google Scholar 

  131. Jo, C. et al. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat. Commun. 5, 3496 (2014).

    Article  PubMed  Google Scholar 

  132. Pickford, F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest. 118, 2190–2199 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Winslow, A. R. et al. α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J. Cell Biol. 190, 1023–1037 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Buchan, J. R., Kolaitis, R.-M., Taylor, J. P. & Parker, R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153, 1461–1474 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Shibutani, S. T., Saitoh, T., Nowag, H., Münz, C. & Yoshimori, T. Autophagy and autophagy-related proteins in the immune system. Nat. Immunol. 16, 1014–1024 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Dong, X. & Levine, B. Autophagy and viruses: adversaries or allies? J. Innate Immun. 5, 480–493 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Choy, A. et al. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338, 1072–1076 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ogawa, M. et al. Escape of intracellular Shigella from autophagy. Science 307, 727–731 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Xu, Y. et al. A bacterial effector reveals the V-ATPase-ATG16L1 axis that initiates xenophagy. Cell 178, 552–566.e20 (2019).

    Article  CAS  PubMed  Google Scholar 

  141. Xu, Y. et al. ARF GTPases activate Salmonella effector SopF to ADP-ribosylate host V-ATPase and inhibit endomembrane damage-induced autophagy. Nat. Struct. Mol. Biol. 29, 67–77 (2022).

    Article  CAS  PubMed  Google Scholar 

  142. Cemma, M. & Brumell, J. H. Interactions of pathogenic bacteria with autophagy systems. Curr. Biol. 22, R540–R545 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Birmingham, C. L., Smith, A. C., Bakowski, M. A., Yoshimori, T. & Brumell, J. H. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J. Biol. Chem. 281, 11374–11383 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Biering, S. B. et al. Viral replication complexes are targeted by LC3-guided interferon-inducible GTPases. Cell Host Microbe 22, 74–85.e7 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sagnier, S. et al. Autophagy restricts HIV-1 infection by selectively degrading Tat in CD4 + T lymphocytes. J. Virol. 89, 615–625 (2015).

    Article  PubMed  Google Scholar 

  146. Birmingham, C. L. & Brumell, J. H. Autophagy recognizes intracellular Salmonella enterica serovar Typhimurium in damaged vacuoles. Autophagy 2, 156–158 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Perrin, A. J., Jiang, X., Birmingham, C. L., So, N. S. Y. & Brumell, J. H. Recognition of bacteria in the cytosol of Mammalian cells by the ubiquitin system. Curr. Biol. 14, 806–811 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Fujita, N. et al. Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin. J. Cell Biol. 203, 115–128 (2013). This study shows that a damaged endosomal membrane causes ubiquitin-coating and autophagosomal membrane formation on the targets for selective autophagy using the artificial polystyrene beads coated with transfection reagent, which damages the membrane.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Thurston, T. L. M., Wandel, M. P., von Muhlinen, N., Foeglein, Á. & Randow, F. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482, 414–418 (2012). This study show that galectin 8 works as a danger receptor for invading bacteria. It promotes early recruitment of NDP52 to the invading bacteria via the galectin 8-binding domain of NDP52, which further facilitates subsequent binding of NDP52 with ubiquitin-coated bacteria.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Lin, C.-Y. et al. Autophagy receptor tollip facilitates bacterial autophagy by recruiting Galectin-7 in response to group A streptococcus infection. Front. Cell Infect. Microbiol. 10, 583137 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Chai, Q. et al. A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy. Nat. Commun. 10, 1973 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Yamada, A., Hikichi, M., Nozawa, T. & Nakagawa, I. FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan. EMBO Rep. 22, e52584 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Otten, E. G. et al. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature 594, 111–116 (2021). This study shows that bacterial lipopolysaccharide, a non-proteinaceous substrate, is ubiquitylated upon bacterial invasion to promote their clearance by xenophagy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. von Muhlinen, N. et al. LC3C, bound selectively by a noncanonical LIR motif in NDP52, is required for antibacterial autophagy. Mol. Cell 48, 329–342 (2012).

    Article  Google Scholar 

  155. Zheng, Y. T. et al. The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J. Immunol. 183, 5909–5916 (2009). This is a classic study that establishes that receptor protein p62 is recruited to invading Salmonella and facilitate their autophagic degradation.

    Article  CAS  PubMed  Google Scholar 

  156. Verlhac, P. et al. Autophagy receptor NDP52 regulates pathogen-containing autophagosome maturation. Cell Host Microbe 17, 515–525 (2015).

    Article  CAS  PubMed  Google Scholar 

  157. Cemma, M., Kim, P. K. & Brumell, J. H. The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway. Autophagy 7, 341–345 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Tumbarello, D. A. et al. The autophagy receptor TAX1BP1 and the molecular motor myosin VI are required for clearance of Salmonella typhimurium by autophagy. PLoS Pathog. 11, e1005174 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Lin, C.-Y. et al. LAMTOR2/LAMTOR1 complex is required for TAX1BP1-mediated xenophagy. Cell Microbiol. 21, e12981 (2019).

    Article  PubMed  Google Scholar 

  160. Manzanillo, P. S. et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501, 512–516 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Franco, L. H. et al. The ubiquitin ligase Smurf1 functions in selective autophagy of Mycobacterium tuberculosis and anti-tuberculous host defense. Cell Host Microbe 21, 59–72 (2017).

    Article  CAS  PubMed  Google Scholar 

  162. Huett, A. et al. The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium. Cell Host Microbe 12, 778–790 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Heath, R. J. et al. RNF166 determines recruitment of adaptor proteins during antibacterial autophagy. Cell Rep. 17, 2183–2194 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Fiskin, E., Bionda, T., Dikic, I. & Behrends, C. Global analysis of host and bacterial ubiquitinome in response to Salmonella typhimurium infection. Mol. Cell 62, 967–981 (2016).

    Article  CAS  PubMed  Google Scholar 

  165. Noad, J. et al. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB. Nat. Microbiol. 2, 17063 (2017). This study shows that ubiquitin-coated invading Salmonella are subsequently labelled by linear, M1-linked polyubiquitin chains by LUBAC, promoting activation of the NF-κB signalling pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Fuseya, Y. et al. The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC. Nat. Cell Biol. 22, 663–673 (2020).

    Article  CAS  PubMed  Google Scholar 

  167. Shahnazari, S. et al. A diacylglycerol-dependent signaling pathway contributes to regulation of antibacterial autophagy. Cell Host Microbe 8, 137–146 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Khaminets, A. et al. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522, 354–358 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. Grumati, P. et al. Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy. eLife 6, e25555 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Fumagalli, F. et al. Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. Nat. Cell Biol. 18, 1173–1184 (2016).

    Article  CAS  PubMed  Google Scholar 

  171. An, H. et al. TEX264 is an endoplasmic reticulum-resident ATG8-interacting protein critical for ER remodeling during nutrient stress. Mol. Cell 74, 891–908.e10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Chino, H., Hatta, T., Natsume, T. & Mizushima, N. Intrinsically disordered protein TEX264 mediates ER-phagy. Mol. Cell 74, 909–921.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  173. Chen, Q. et al. ATL3 is a tubular ER-phagy receptor for GABARAP-mediated selective autophagy. Curr. Biol. 29, 846–855.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  174. Smith, M. D. et al. CCPG1 is a non-canonical autophagy cargo receptor essential for ER-phagy and pancreatic ER proteostasis. Dev. Cell 44, 217–232.e11 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Nthiga, T. M. et al. CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy. EMBO J. 39, e103649 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Yang, H. et al. Sequestosome 1/p62 protein is associated with autophagic removal of excess hepatic endoplasmic reticulum in mice. J. Biol. Chem. 291, 18663–18674 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Ji, C. H. et al. The N-degron pathway mediates ER-phagy. Mol. Cell 75, 1058–1072.e9 (2019).

    Article  CAS  PubMed  Google Scholar 

  178. Liang, J. R. et al. A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-resident UFMylation. Cell 180, 1160–1177.e20 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Stephani, M. et al. A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress. eLife 9, e58396 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Deosaran, E. et al. NBR1 acts as an autophagy receptor for peroxisomes. J. Cell Sci. 126, 939–952 (2013).

    CAS  PubMed  Google Scholar 

  181. Yamashita, S., Abe, K., Tatemichi, Y. & Fujiki, Y. The membrane peroxin PEX3 induces peroxisome-ubiquitination-linked pexophagy. Autophagy 10, 1549–1564 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Kim, P. K., Hailey, D. W., Mullen, R. T. & Lippincott-Schwartz, J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc. Natl Acad. Sci. USA 105, 20567–20574 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Sargent, G. et al. PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation. J. Cell Biol. 214, 677–690 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Zhang, J. et al. ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat. Cell Biol. 17, 1259–1269 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Zheng, J., Chen, X., Liu, Q., Zhong, G. & Zhuang, M. Ubiquitin ligase MARCH5 localizes to peroxisomes to regulate pexophagy. J. Cell Biol. 221, e202103156 (2022).

    Article  CAS  PubMed  Google Scholar 

  186. Hara-Kuge, S. & Fujiki, Y. The peroxin Pex14p is involved in LC3-dependent degradation of mammalian peroxisomes. Exp. Cell Res. 314, 3531–3541 (2008).

    Article  CAS  PubMed  Google Scholar 

  187. Nakatogawa, H. Spoon-feeding ribosomes to autophagy. Mol. Cell 71, 197–199 (2018).

    Article  CAS  PubMed  Google Scholar 

  188. An, H. & Harper, J. W. Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy. Nat. Cell Biol. 20, 135–143 (2018).

    Article  CAS  PubMed  Google Scholar 

  189. Wyant, G. A. et al. NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science 360, 751–758 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. An, H., Ordureau, A., Körner, M., Paulo, J. A. & Harper, J. W. Systematic quantitative analysis of ribosome inventory during nutrient stress. Nature 583, 303–309 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Maio, N. & Rouault, T. A. Outlining the complex pathway of mammalian Fe-S cluster biogenesis. Trends Biochem. Sci. 45, 411–426 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Kaur, J. & Debnath, J. Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461–472 (2015).

    Article  CAS  PubMed  Google Scholar 

  193. Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W. & Kimmelman, A. C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014). This work is the first to identify NCOA4 as a receptor protein for the autophagic degradation of ferritin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Mancias, J. D. et al. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. eLife 4, e10308 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Goodwin, J. M. et al. Autophagy-independent lysosomal targeting regulated by ULK1/2-FIP200 and ATG9. Cell Rep. 20, 2341–2356 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Koutsifeli, P. et al. Glycogen-autophagy: molecular machinery and cellular mechanisms of glycophagy. J. Biol. Chem. 298, 102093 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Heden, T. D., Chow, L. S., Hughey, C. C. & Mashek, D. G. Regulation and role of glycophagy in skeletal muscle energy metabolism. Autophagy 18, 1078–1089 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Jiang, S. et al. Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism. J. Biol. Chem. 285, 34960–34971 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Jiang, S., Wells, C. D. & Roach, P. J. Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochem. Biophys. Res. Commun. 413, 420–425 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Han, Z. et al. Model-based analysis uncovers mutations altering autophagy selectivity in human cancer. Nat. Commun. 12, 3258 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Mellor, K. M., Varma, U., Stapleton, D. I. & Delbridge, L. M. D. Cardiomyocyte glycophagy is regulated by insulin and exposure to high extracellular glucose. Am. J. Physiol. Heart Circ. Physiol. 306, H1240–H1245 (2014).

    Article  CAS  PubMed  Google Scholar 

  202. Mellor, K. M. et al. Protective role Atg8 homologue Gabarapl1 regulating cardiomyocyte glycophagy in diabetic heart disease. Preprint at bioRxiv https://doi.org/10.1101/2021.06.21.449174 (2021).

    Article  Google Scholar 

  203. Herker, E., Vieyres, G., Beller, M., Krahmer, N. & Bohnert, M. Lipid droplet contact sites in health and disease. Trends Cell Biol. 31, 345–358 (2021).

    Article  CAS  PubMed  Google Scholar 

  204. Olzmann, J. A. & Carvalho, P. Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol. 20, 137–155 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Tauchi-Sato, K., Ozeki, S., Houjou, T., Taguchi, R. & Fujimoto, T. The surface of lipid droplets is a phospholipid monolayer with a unique fatty acid composition. J. Biol. Chem. 277, 44507–44512 (2002).

    Article  CAS  PubMed  Google Scholar 

  206. Choudhary, V., Ojha, N., Golden, A. & Prinz, W. A. A conserved family of proteins facilitates nascent lipid droplet budding from the ER. J. Cell Biol. 211, 261–271 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Szymanski, K. M. et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc. Natl Acad. Sci. USA 104, 20890–20895 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Zechner, R., Madeo, F. & Kratky, D. Cytosolic lipolysis and lipophagy: two sides of the same coin. Nat. Rev. Mol. Cell Biol. 18, 671–684 (2017).

    Article  CAS  PubMed  Google Scholar 

  210. Schott, M. B. et al. Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes. J. Cell Biol. 218, 3320–3335 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Robichaud, S. et al. Identification of novel lipid droplet factors that regulate lipophagy and cholesterol efflux in macrophage foam cells. Autophagy 17, 3671–3689 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Bersuker, K. et al. A proximity labeling strategy provides insights into the composition and dynamics of lipid droplet proteomes. Dev. Cell 44, 97–112.e7 (2018).

    Article  CAS  PubMed  Google Scholar 

  213. Wang, L. et al. Ethanol-triggered lipophagy requires SQSTM1 in AML12 hepatic cells. Sci. Rep. 7, 12307 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Berardi, D. et al. BNIP3 attenuates hepatocellular carcinoma by promoting lipid droplet turnover at the lysosome. Res. Sq. https://doi.org/10.21203/rs.3.rs-947988/v1 (2021).

    Article  Google Scholar 

  215. Chang, C. et al. Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy. Sci. Adv. 7, eabg4922 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Sawa-Makarska, J. et al. Reconstitution of autophagosome nucleation defines Atg9 vesicles as seeds for membrane formation. Science 369, eaaz7714 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Farré, J.-C. & Subramani, S. Mechanistic insights into selective autophagy pathways: lessons from yeast. Nat. Rev. Mol. Cell Biol. 17, 537–552 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Torggler, R. et al. Two independent pathways within selective autophagy converge to activate Atg1 kinase at the vacuole. Mol. Cell 64, 221–235 (2016).

    Article  CAS  PubMed  Google Scholar 

  219. Kamber, R. A., Shoemaker, C. J. & Denic, V. Receptor-bound targets of selective autophagy use a Scaffold protein to activate the Atg1 kinase. Mol. Cell 59, 372–381 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Pan, Z. Q. et al. Atg1 kinase in fission yeast is activated by atg11-mediated dimerization and cis-autophosphorylation. eLife 9, e58073 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Nakatogawa, H. Mechanisms governing autophagosome biogenesis. Nat. Rev. Mol. Cell Biol. 21, 439–458 (2020).

    Article  CAS  PubMed  Google Scholar 

  222. Takahashi, D. et al. AUTACs: cargo-specific degraders using selective autophagy. Mol. Cell 76, 797–810.e10 (2019).

    Article  CAS  PubMed  Google Scholar 

  223. Li, Z. et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 575, 203–209 (2019).

    Article  CAS  PubMed  Google Scholar 

  224. Wong, Y. C. & Holzbaur, E. L. F. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc. Natl Acad. Sci. USA 111, E4439–E4448 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Radulovic, M. et al. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. 37, e99753 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Medina, D. L. et al. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat. Cell Biol. 17, 288–299 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Nakamura, S. et al. LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury. Nat. Cell Biol. 22, 1252–1263 (2020).

    Article  CAS  PubMed  Google Scholar 

  228. Papadopoulos, C., Kravic, B. & Meyer, H. Repair or lysophagy: dealing with damaged lysosomes. J. Mol. Biol. 432, 231–239 (2020).

    Article  CAS  PubMed  Google Scholar 

  229. Kluge, A. F. et al. Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy. Bioorg. Med. Chem. Lett. 28, 2655–2659 (2018).

    Article  CAS  PubMed  Google Scholar 

  230. Ciechanover, A. & Kwon, Y. T. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp. Mol. Med. 47, e147 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Meijer, A. J. & Codogno, P. Regulation and role of autophagy in mammalian cells. Int. J. Biochem. Cell Biol. 36, 2445–2462 (2004).

    Article  CAS  PubMed  Google Scholar 

  232. Burslem, G. M. & Crews, C. M. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 181, 102–114 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Intramural Program of the National Institute of Neurological Disorders and Stroke.

Author information

Author notes

  1. These authors contributed equally: Jose Norberto S Vargas, Maho Hamasaki.

Authors and Affiliations

  1. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK

    Jose Norberto S. Vargas

  2. UK Dementia Research Institute, University College London, London, UK

    Jose Norberto S. Vargas

  3. Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Jose Norberto S. Vargas & Richard J. Youle

  4. Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan

    Maho Hamasaki & Tamotsu Yoshimori

  5. Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

    Maho Hamasaki & Tamotsu Yoshimori

  6. Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan

    Tsuyoshi Kawabata

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  1. Jose Norberto S. Vargas
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M.H., T.K. and T.Y. wrote and edited the sections on introduction, lysophagy and xenophagy, and created the figures and a table associated with these sections. J.N.S.V. and R.J.Y. wrote and edited the sections on mitophagy, aggrephagy, autophagy of other cellular structures, therapeutic opportunities, and conclusions and perspectives, and created the figures associated with these sections.

Corresponding authors

Correspondence to Maho Hamasaki, Richard J. Youle or Tamotsu Yoshimori.

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Nature Reviews Molecular Cell Biology thanks Zvulun Elazar, Hong Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

LC3/GABARAP proteins

Mammalian paralogs of Atg8 protein. There are over six paralogs of Atg8 in mammals. The paralogs are activated by the processing of the C-terminal residue of LC3 paralogs, exposing G residue that is modified with phosphatidylethanolamine. LC3-phosphatidylethanolamine stably binds to autophagosome and facilitates autophagosome formation and maturation.

TOM and TIM complex

A mitochondrial protein complexe that facilitates the translocation of cytosolic proteins containing a mitochondrial-targeting sequence into the mitochondria.

p97

A protein, member of the AAA-ATPase, also known as valosin-containing protein (VCP) or cdc48.

Reticulocyte

The immature form of red blood cells (erythrocytes) still containing RNA. It is generated from progenitor cells via erythropoiesis, a process accompanied by enucleation in mammals.

ATG9A

A transmembrane protein with a phospholipid scramblase activity that plays a key role in the initiation of autophagy through the delivery of membranes to growing autophagosomes.

ULK1 complex

A protein kinase complex consists of ULK1 kinase, ATG13, ATG101 and FIP200. It promotes the early step of autophagy by facilitating the formation of an isolation membrane.

Mitochondrial antiviral signalling protein

(MAVS). A protein localized on the outer membrane of the mitochondria and activated by viral RNA, leading to increased levels of pro-inflammatory cytokines.

VDAC1

A protein forming a voltage-dependent ion channel on the outer mitochondrial membrane. VDACs are responsible for the transport of nucleotides and metabolites from the cytosol into the mitochondria.

Damage-associated molecular patterns

(DAMPs). Various molecules released during cell death via infection or damage. For instance, mitochondrial DNA released by apoptotic cells act as a DAMP and are recognized by Toll-like receptor 9 expressed by other cells, leading to inflammatory responses.

Amyloid-β

A large transmembrane protein that accumulates in the brain of patients with Alzheimer disease forming amyloid plaques — suggested causative agents of neurodegeneration in Alzheimer disease.

LLOMe

A dipeptide that is activated by lysosome enzyme like cathepsin and ruptures lysosomal membrane.

Galectins

Proteins termed S-type lectins, which bind β-galactoside carbohydrates. They bind to glycoproteins on the inner membrane of endosomes; therefore, endosomal membrane rupture causes the accumulation of galectins, acting as a danger signal provoking selective autophagy.

E3 ubiquitin ligases

Enzymes that selectively modify proteins by covalently attaching ubiquitin.

Beclin 1

The mammalian homologue of yeast Atg6, a component of class III phosphoinositide 3-kinase (PI3K) complex. The BECN1 gene, encoding beclin 1, is located at a locus closed to the BRCA1 tumour suppressor gene and is therefore often deleted together with BRCA1 in breast cancer.

ESCRT-III complex

Long filamentous complex promoting membrane remodelling, nucleation and scission to facilitate endocytosis or generation of multivesicular bodies together with other ESCRT complexes.

Endo-lysosomal damage response

(ELDR). Cellular response triggered by lysosomal damage. ELDR complex contains ubiquitin-directed AAA-ATPase p97, deubiquitinating enzyme YOD1, and cofactors UBXD1 and PLAA.

Multisystem proteinopathy

Defined as a combination of multiple degenerative disorders, such as amyotrophic lateral sclerosis (ALS) and inclusion body myopathy, characterized by the presence of protein aggregates in various organs, including muscle, bone and the central nervous system.

E2 ubiquitin-conjugating enzyme

Enzyme that transfers ubiquitin from ubiquitin-activation enzyme E1 to a target protein through the support of E3.

α-Synuclein

Neuronal protein that regulates synaptic vesicle trafficking and neurotransmitter release. Aggregates of α-synuclein establish insoluble fibrils, which are found in patients with Parkinson disease.

Tau

Protein that functions to stabilize microtubules in axons. When hyperphosphorylated, it forms insoluble aggregates, causative of neurodegenerative diseases such as Alzheimer disease and Parkinson disease.

Huntingtin

Protein involves in axonal transport. Mutants that show expansion of poly-glutamine repeats are causative of Huntington disease.

Cytochrome c

Haeme protein attached to the inner membrane of a mitochondrion. In response to an apoptotic signal, it is released into the cytoplasm and activates caspase 9.

Chaperone-mediated autophagy

A mode of autophagy that utilizes cytosolic HSC70 protein, which binds to targets and the lysosomal membrane protein LAMP2A. It is distinguished from macroautophagy, which is often referred to as just autophagy. Chaperone-mediated autophagy facilitates protein degradation via direct incorporation of proteins without the formation of the autophagosome.

TDP43

An RNA-binding protein that is mutated in ALS. Furthermore, the aggregation of this protein is the neuropathological hallmark of ALS and frontotemporal dementia.

FUS

A protein that functions as an RNA-binding protein. Mutations in FUS lead to early onset ALS.

AMPK

A kinase activated upon stresses that reduce cellular ATP levels to promote a line of pathways that protect cells from the stresses. AMPK and mTOR cooperatively regulate autophagy.

Cytosolic-to-vacuole targeting pathway

A pathway responsible for delivering some cytosolic proteins into vacuoles in yeast. Sharing certain components required for macroautophagy, cytosolic-to-vacuole targeting is considered one form of selective autophagy.

Proteolysis-targeting chimaeras

Heterobifunctional molecules that target E3 ligase complexes to specific substrates to induce the ubiquitylation and subsequent proteasomal degradation of the target.

Lipopolysaccharide

A major component of outer membranes of Gram-negative bacteria. It consists of lipid A, oligosaccharide and the O-antigen. The structure of lipid A and oligosaccharide is shared among many bacteria but that of O-antigen is variable.

NEMO

A protein that is involved in the kinase complex, which facilitates activation of NF-κB. It phosphorylates IκB, invoking nuclear translocation of NF-κB.

mTOR

A protein kinase that senses cellular metabolism, such as nutrients, energy and hormone levels, or exogenous stresses, thereby regulating a variety of cellular actions such as protein synthesis, proliferation, endocytosis and autophagy. mTOR binds to other subunits to form complexes called mTORC1 and mTORC2.

Foam cells

Macrophages containing cholesterol and observed during arteriosclerotic vascular disease.

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Vargas, J.N.S., Hamasaki, M., Kawabata, T. et al. The mechanisms and roles of selective autophagy in mammals. Nat Rev Mol Cell Biol 24, 167–185 (2023). https://doi.org/10.1038/s41580-022-00542-2

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