Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy

doi:10.1016/j.molcel.2019.02.010

. 2019 Apr 18;74(2):347-362.e6.

doi: 10.1016/j.molcel.2019.02.010. Epub 2019 Mar 7.

Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy

Jose Norberto S Vargas¹, Chunxin Wang², Eric Bunker², Ling Hao², Dragan Maric³, Giampietro Schiavo⁴, Felix Randow⁵, Richard J Youle⁶

Affiliations

¹ Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.
² Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
³ Flow and Imaging Cytometry Core Facility, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA.
⁴ Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK; UK Dementia Research Institute at UCL, UCL Queen Square Institute of Neurology, University College London, London WC1E 6BT, UK; Discoveries Centre for Regenerative and Precision Medicine, UCL Campus, University College London, London WC1E 6BT, UK.
⁵ MRC Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge CB2 0QH, UK; University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
⁶ Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: youler@ninds.nih.gov.

PMID: 30853401
PMCID: PMC6642318
DOI: 10.1016/j.molcel.2019.02.010

Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy

Jose Norberto S Vargas et al. Mol Cell. 2019.

. 2019 Apr 18;74(2):347-362.e6.

doi: 10.1016/j.molcel.2019.02.010. Epub 2019 Mar 7.

Authors

Jose Norberto S Vargas¹, Chunxin Wang², Eric Bunker², Ling Hao², Dragan Maric³, Giampietro Schiavo⁴, Felix Randow⁵, Richard J Youle⁶

Affiliations

¹ Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.
² Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
³ Flow and Imaging Cytometry Core Facility, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA.
⁴ Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK; UK Dementia Research Institute at UCL, UCL Queen Square Institute of Neurology, University College London, London WC1E 6BT, UK; Discoveries Centre for Regenerative and Precision Medicine, UCL Campus, University College London, London WC1E 6BT, UK.
⁵ MRC Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge CB2 0QH, UK; University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
⁶ Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: youler@ninds.nih.gov.

PMID: 30853401
PMCID: PMC6642318
DOI: 10.1016/j.molcel.2019.02.010

Abstract

Selective autophagy recycles damaged organelles and clears intracellular pathogens to prevent their aberrant accumulation. How ULK1 kinase is targeted and activated during selective autophagic events remains to be elucidated. In this study, we used chemically inducible dimerization (CID) assays in tandem with CRISPR KO lines to systematically analyze the molecular basis of selective autophagosome biogenesis. We demonstrate that ectopic placement of NDP52 on mitochondria or peroxisomes is sufficient to initiate selective autophagy by focally localizing and activating the ULK1 complex. The capability of NDP52 to induce mitophagy is dependent on its interaction with the FIP200/ULK1 complex, which is facilitated by TBK1. Ectopically tethering ULK1 to cargo bypasses the requirement for autophagy receptors and TBK1. Focal activation of ULK1 occurs independently of AMPK and mTOR. Our findings provide a parsimonious model of selective autophagy, which highlights the coordination of ULK1 complex localization by autophagy receptors and TBK1 as principal drivers of targeted autophagosome biogenesis.

Keywords: ATG13; FIP200; P62; PINK1; Parkin; TAX1BP1; lysosome; mitochondria; mitophagy; optineurin.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Ectopic Recruitment of NDP52 to Mitochondria Can Initiate Mitophagy by Recruiting ATG Machinery (A) Schematic of chemically inducible dimerization assay to control mitochondrial localization of NDP52. (B) Live confocal imaging of HeLa cells stably expressing mito-mKeima and FRB-Fis1 and transiently expressing FKBP-GFP-NDP52. Cells were treated with Rapalog for 24 h. Cytosolic mitochondria (488 nm; red) and mitolysosomes (561 nm; purple) are shown. (C) FACS plots showing mito-mKeima ratio (561/488 nm). HeLa cells stably expressing mito-mKeima, FRB-Fis1, and FKBP-GFP-NDP52 were treated with Rapalog for 24 h. (D) Quantification of mito-mKeima ratiometric FACS analysis of WT or PINK1 KO HeLa cells stably expressing mito-mKeima, FRB-Fis1, and FKBP-GFP-NDP52 after 24 h of Rapalog treatment. n = 3 biological replicates. (E–G) Confocal images of HeLa cells stably expressing mito-mKeima, FRB-Fis1, and FKBP-GFP-NDP52. Cells were transfected with (E) HA-FIP200, (F) HA-ATG14, and (G) Flag-ATG16L1. Cells were then treated with Rapalog for 24 h, fixed, then immunostained for Tom20 with either HA or Flag. (H) Quantification of FIP200 recruitment to mitochondria by Pearson’s correlation coefficient as in (E). (I) Quantification of ATG14 recruitment to mitochondria by Pearson’s correlation coefficient as in (F). (J) Quantification of the number of ATG16L1 foci on mitochondria before and after Rapalog treatment as in (G). Arrows indicate foci of ATG16L1 colocalized with Tom20. All FACS quantifications: n = 3. Data are represented as mean ± SD. p value: ^∗ = < 0.05; ^∗∗ < 0.01; ^∗∗∗ < 0.001; ^∗∗∗∗ < 0.00001; ns., not significant. Scale bars: 10 μm. See also Figure S1.

**Figure 2**
NDP52 Interacts with ULK1 Complex through FIP200 (A and B) Western analysis of immunoprecipitation assay of endogenous FIP200 (B) or ULK1 (A) in HeLa cells. (C) Endogenous immunoprecipitation of NDP52 from WT HeLa cells treated with oligomycin/antimycin (OA) and Bafilomycin (200 nM; to prevent receptor degradation) for 3 h. Cells were crosslinked *in situ* using DSP prior to immunoprecipitation and western blot analysis. (D) Western analysis of immunoprecipitation assay for NDP52 in either WT or FIP200 KO HeLa cells. See also Figure S1.

**Figure 3**
Mutational Dissection of NDP52-FIP200 Interaction (A) Diagram of NDP52 mutation and deletions. ΔSKICH is a deletion from position 1–127. ΔSKICH ΔCLIR is a deletion from 1–148. CLIR null is a V136S mutation in the LC3C binding domain. LIR-like null pertains to AAAA substitution of DYWE at position 203–206 within the non-canonical LIR domain. C425A is a mutation in ubiquitin-binding ZF2 motif. Diagram of FIP200 mutations and deletions. Q4A refers to 4 alanine substitutions within the ATG13-binding domain. LZA refers to 4 alanine mutations in the leucine zipper domain. (B) Western analysis of Flag-NDP52 WT and mutants (see Figure 3H for NDP52 mutation map), and HA-FIP200 were transiently transfected in HEK293T cells followed by HA immunoprecipitation. (C) Western analysis of HA-FIP200 immunoprecipitation performed on HEK293T cells overexpressing HA-FIP200 and GFP-NDP52 or GFP-NDP52 CLIR/LIR-like null. Arrow indicates NDP52 band. Asterisks indicate background bands. (D) Western blot analysis of HEK293T cells transfected with full-length, N1 (1–800), and C1 (800–1,591) HA-FIP200 co-transfected with Flag-NDP52, then subjected to HA immunoprecipitation. (E) Western blot analysis after HA immunoprecipitation performed in HEK293T cells transfected with HA-FIP200 C1 (800–1,591), C2 (1,300–1,591), C3 (1,400–1,591) and Flag-NDP52. (F) Western blot analysis after HA immunoprecipitation performed on HEK293T cells transfected with HA-LZ (1,286–1,413 of FIP200), HA-LZA (1,286–1,413 of FIP200; AAAA substitution at positions 1,371, 1,378, 1,385, and 1,392) and Flag-NDP52. (G) Western blot analysis after HA immunoprecipitation performed on HEK293T cells transfected with full-length HA-FIP200, HA-FIP200 Q4A (full-length FIP200 with AAAA substitutions at positions 582–585), HA-FIP200 LZA (full-length FIP200 with AAAA substitution at positions 1,371, 1,378, 1,385, 1,392), and Flag-NDP52. (H) Confocal imaging of WT HeLa cells stably expressing mCherry-Parkin and GFP-NDP52 and transiently transfected with WT FIP200 leucine zipper (HA-LZ) or alanine mutant (HA-LZA), then treated with OA for 3 h. Cells were then fixed and stained for HA. Scale bars: 10 μm. See also Figures S1 and S2.

**Figure 4**
NDP52 Mediates Autophagosome Biogenesis on Cargo Organelle Independent of LC3 (A and B) Quantification of FACS ratiometric analysis of mito-mKeima after 24 h treatment of Rapalog. HeLa cells stably expressing FRB-Fis1, mito-mKeima, and FKBP-GFP-NDP52 WT and ΔSKICH in (A) or FKBP-GFP-NDP52 CLIR/LIR-like null in (B). (C) Quantification of DFCP1 foci. WT or 6KO (LC3/GABARAP hexa KO) cells expressing GFP-DFCP1 were analyzed at basal conditions or after 3 h OA. (D) Confocal imaging of WT or 6KO HeLa cells transiently expressing GFP-ULK1, GFP-FIP200, or GFP-DFCP1, as well as HA-Parkin. Cells were immunostained for HA. (E–G) Pearson’s correlation or automated counting of overlapping puncta between FIP200 (E), ULK1 (F), or DFCP1 (G) on Parkin before or after OA treatment. (H and I) Quantification of FACS ratiometric analysis of mito-mKeima. FKBP-GFP-ULK1 (I) or NDP52 (H) were stably expressed with FRB-Fis1 and mito-mKeima in WT or 6KO cells. Cells were then treated with Rapalog for 24 h. (J) NDP52 WT and mutants, as well as mito-mKeima, were stably expressed in OPTN, NDP52, Tax1bp1 triple KO cells (TKO). Cells were treated with OA for 6 h then analyzed by FACS for mitophagy. All FACS quantifications: n = 3. Data are represented as mean ± SD. p value: ^∗ = < 0.05; ^∗∗ < 0.01; ^∗∗∗ < 0.001; ^∗∗∗∗ < 0.00001; ns., not significant. Scale bars: 10 μm. See also Figures S2 and S5.

**Figure 5**
ULK1 Autoactivation by Ectopic Localization Elicits Mitophagy (A) WT or AMPK DKO U2OS cells stably expressing YFP-Parkin were either treated with OA or starved in HBSS for 18 h followed by western blot analysis of mitochondrial proteins to measure mitophagy. (B) Cells in (A) also stably expressing mito-mKeima were treated with OA for 6 h, then analyzed by FACS for mito-mKeima 561/488 nm ratio. (C) FACS analysis plots of HeLa cells expressing YFP-Parkin and mito-mKeima after 4 h treatment of OA or starvation showing no mitophagy detected after starvation. (D) Cells in (C) were treated with OA or OA with ULK1/2 inhibitor for 5 h followed by FACS analysis. (E) Quantification of FACS ratiometric analysis of mito-mKeima of WT or AMPK DKO U2OS cells stably expressing FKBP-GFP-ULK1, FRB-Fis1, and mito-mKeima treated with Rapalog for 24 h. (F) Quantification of FACS ratiometric analysis of mito-mKeima of HeLa cells expressing FKBP-GFP-ULK1 (WT or T180A), FRB-Fis1, and mito-mKeima treated with Rapalog for 24 h. (G) FACS analysis of mito-mKeima. HeLa cells expressing FKBP-GFP-ULK1, FRB-Fis1, and mito-mKeima were treated with Rapalog for 24 h in the presence or absence of ULK1/2 inhibitor (MRT68921, 1 μM). (H) Quantification of FACS mito-mKeima analysis of WT or AMPK DKO U2OS cells expressing FKBP-GFP-NDP52, FRB-Fis1, and mito-mKeima treated with Rapalog for 24 h. (I) WT and AMPK DKO U2OS cells expressing FKBP-GFP-FBD, FRB-Fis1, and mito-mKeima were treated with Rapalog for 8, 24, and 48 h. COXII levels were then analyzed by western blot to measure mitophagy. (J) FACS plot of mito-mKeima mitophagy analysis. Cells expressing YFP-Parkin and mito-mKeima were treated with Torin1 for 3 h. (K) Western analysis of HeLa cells expressing FKBP-GFP-FBD, FRB-Fis1, and mito-mKeima, as well as myc-mTOR. Cells were treated with Rapalog or concurrently with Torin1 (1 μM) for 24 h. (L) FACS analysis for mito-mKeima of cells expressing FKBP-GFP-FBD, FRB-Fis1, mito-mKeima, and myc-mTOR. (M) HeLa expressing FKBP-GFP-ULK1, FRB-Fis1, and myc-mTOR were analyzed for mito-mKeima signal by FACS. All FACS quantifications: n = 3 biological replicates. Data are represented as mean ± SD. p value: ^∗ = < 0.05; ^∗∗ < 0.01; ^∗∗∗ < 0.001; ^∗∗∗∗ < 0.00001; ns., not significant. See also Figures S3, S4, and S7.

**Figure 6**
TBK1 Mediates NDP52-ULK1 Complex Mitophagy (A) Quantification of FACS ratiometric analysis of mito-mKeima. WT, FIP200 KO, TKO (OPTN, NDP52 Tax1bp1 triple KO), or TBK1 KO cells stably expressing FKBP-GFP-NDP52, FRB-Fis1, and mito-mKeima treated with Rapalog for 24 h. (B) Quantification of FACS analysis of mito-mKeima. WT and KO cells as in (A), stably expressing FKBP-GFP-ULK1, FRB-Fis1, and mito-mKeima treated with 24 h Rapalog. (C) Western analysis of HA-FIP200 immunoprecipitation in WT or TBK1 KO HeLa cells. Endogenous NDP52 and TBK1 are immunoblotted. (D) FACS plots of mito-mKeima ratiometric analysis. WT or TBK1 KO cells stably expressing mito-mKeima and YFP-Parkin, and transiently expressing BFP-NDP52 were treated with OA for 3 h. (E) Western analysis. Cells stably expressing mCherry-Parkin with or without GFP-NDP52 were treated with OA for 6 h. (F) Quantification of FACS ratiometric analysis of mito-mKeima. WT, FIP200 KO, TKO, or TBK1 KO cells, all stably expressing mito-mKeima and YFP-Parkin, were treated with OA for 6 or 24 h. (G) Quantification of FACS ratiometric analysis of mito-mKeima. Cells stably expressing FRB-Fis1 and either WT FKBP-GFP-TBK1 or kinase-dead FKBP-GFP-TBK1 K38M were treated with Rapalog for 24 h. (H) mito-mKeima FACS analysis of cells stably expressing FRB-Fis1 and FKBP-TBK1 after mitochondrial localization of TBK1 with Rapalog with or without ULK1/2 inhibitor, MRT68921 at 1 μM. (I) Quantification of FACS ratiometric analysis of mito-mKeima of WT or TKO stably expressing FRB-Fis1 and WT FKBP-GFP-TBK1. (J) FACS analysis of cells expressing WT FKBP-GFP-TBK1 or FKBP-GFP-TBK1 ΔC terminus (Δ 685–729), with FRB-FIs1 and mito-mKeima after 24 h of Rapalog treatment. (K) Quantification of FACS ratiometric analysis of HeLa cells expressing FKBP-GFP-TBK1, FRB-Fis1, and mito-mKeima after 24 h of Rapalog treatment. (L) Model of NDP52/TBK1-mediated recruitment of ULK1 complex during mitophagy resulting from bypass experiments. All FACS quantifications: n = 3 biological replicates, except in (F) n = 2. Data are represented as mean ± SD. p value: ^∗ = < 0.05; ^∗∗ < 0.01; ^∗∗∗ < 0.001; ^∗∗∗∗ < 0.00001; ns., not significant. See also Figures S5, S6, and S7.

**Figure 7**
Chimeric FBD-Parkin Can Compensate for Loss of TBK1 or Receptor Proteins during Mitophagy (A) Model for the bypass experiment performed using FIP200-binding peptide-Parkin (FBD-Parkin) in WT, TBK1 KO, or 5KO (OPTN, NDP52, Tax1bp1, NBR1, p62) cells. (B) Mitophagy analysis by FACS. WT HeLa cells, TBK1 KO, or 5KO cells expressing mito-mKeima and FBD-Parkin. (C and D) (C) FBD-Parkin (E230R/E241R) or (D) FBD-Parkin (K211N) were treated with OA and QVD for 6 h. All FACS quantifications: n = 3 biological replicates. Data are represented as mean ± SD. p value: ^∗ = < 0.05; ^∗∗ < 0.01; ^∗∗∗ < 0.001; ^∗∗∗∗ < 0.00001; ns., not significant. See also Figure S3.

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References

1. Alemu E.A., Lamark T., Torgersen K.M., Birgisdottir A.B., Larsen K.B., Jain A., Olsvik H., Øvervatn A., Kirkin V., Johansen T. ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J. Biol. Chem. 2012;287:39275–39290. - PMC - PubMed
1. Alers S., Löffler A.S., Wesselborg S., Stork B. The incredible ULKs. Cell Commun. Signal. 2012;10:7. - PMC - PubMed
1. Ashrafi G., Schlehe J.S., LaVoie M.J., Schwarz T.L. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J. Cell Biol. 2014;206:655–670. - PMC - PubMed
1. Bach M., Larance M., James D.E., Ramm G. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem. J. 2011;440:283–291. - PubMed
1. Behrends C., Fulda S. Receptor proteins in selective autophagy. Int. J. Cell Biol. 2012;2012:673290. - PMC - PubMed

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[1] Alemu E.A., Lamark T., Torgersen K.M., Birgisdottir A.B., Larsen K.B., Jain A., Olsvik H., Øvervatn A., Kirkin V., Johansen T. ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J. Biol. Chem. 2012;287:39275–39290. - PMC - PubMed

[2] Alemu E.A., Lamark T., Torgersen K.M., Birgisdottir A.B., Larsen K.B., Jain A., Olsvik H., Øvervatn A., Kirkin V., Johansen T. ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J. Biol. Chem. 2012;287:39275–39290. - PMC - PubMed

[3] Alers S., Löffler A.S., Wesselborg S., Stork B. The incredible ULKs. Cell Commun. Signal. 2012;10:7. - PMC - PubMed

[4] Alers S., Löffler A.S., Wesselborg S., Stork B. The incredible ULKs. Cell Commun. Signal. 2012;10:7. - PMC - PubMed

[5] Ashrafi G., Schlehe J.S., LaVoie M.J., Schwarz T.L. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J. Cell Biol. 2014;206:655–670. - PMC - PubMed

[6] Ashrafi G., Schlehe J.S., LaVoie M.J., Schwarz T.L. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J. Cell Biol. 2014;206:655–670. - PMC - PubMed

[7] Bach M., Larance M., James D.E., Ramm G. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem. J. 2011;440:283–291. - PubMed

[8] Bach M., Larance M., James D.E., Ramm G. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem. J. 2011;440:283–291. - PubMed

[9] Behrends C., Fulda S. Receptor proteins in selective autophagy. Int. J. Cell Biol. 2012;2012:673290. - PMC - PubMed

[10] Behrends C., Fulda S. Receptor proteins in selective autophagy. Int. J. Cell Biol. 2012;2012:673290. - PMC - PubMed

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Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy

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Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy

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