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Review
. 2019 Oct;15(10):1682-1693.
doi: 10.1080/15548627.2019.1596479. Epub 2019 Apr 14.

Autophagy-dependent secretion: mechanism, factors secreted, and disease implications

Jacob New  1   2 , Sufi Mary Thomas  1   2   3
Affiliations
Review

Autophagy-dependent secretion: mechanism, factors secreted, and disease implications

Jacob New et al. Autophagy. 2019 Oct.

Abstract

Although best understood as a degradative pathway, recent evidence demonstrates pronounced involvement of the macroautophagic/autophagic molecular machinery in cellular secretion. With either overexpression or inhibition of autophagy mediators, dramatic alterations in the cellular secretory profile occur. This affects secretion of a plethora of factors ranging from cytokines, to granule contents, and even viral particles. Encompassing a wide range of secreted factors, autophagy-dependent secretion is implicated in diseases ranging from cancer to neurodegeneration. With a growing body of evidence shedding light onto the molecular mediators, this review delineates the molecular machinery involved in selective targeting of the autophagosome for either degradation or secretion. In addition, we summarize the current understanding of factors and cargo secreted through this unconventional route, and describe the implications of this pathway in both health and disease. Abbreviations: BECN1, beclin 1; CAF, cancer associated fibroblast; CUPS, compartment for unconventional protein secretion; CXCL, C-X-C motif chemokine ligand; ER, endoplasmic reticulum; FGF2, fibroblast growth factor 2; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IL, Interleukin; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPS, misfolding associated protein secretion; MEF, mouse embryonic fibroblast; MTORC1, MTOR complex I; PtdIns, phosphatidyl inositol; SEC22B, SEC22 homolog B, vesicle trafficking protein (gene/pseudogene); SFV, Semliki forest virus; SNCA, synuclein alpha; SQSTM1, sequestosome 1; STX, Syntaxin; TASCC, TOR-associated spatial coupling compartment; TGFB, transforming growth factor beta; TRIM16, tripartite motif containing 16; UPS, unconventional protein secretion; VWF, von Willebrand factor.

Keywords: Autophagy-dependent secretion; IL1B; cancer; infection; neurodegeneration; secretory autophagy.

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Figures

Figure 1.
Figure 1.
Initiating events in autophagy. The autophagic pathway centers around a convergence of 3 broad initiating events: 1) a catalytic cascade regulated by nutrient sensors, AMPK and MTORC1, leads to the phosphorylation of ULK1 and the subsequent activation of the BECN1 complex, which is essential for membrane nucleation and expansion; 2) the lipidation of LC3, which incorporates as LC3-II into the autophagic membrane; and 3) cargo recruitment by SQSTM1 or another autophagy cargo receptor, which bind primarily ubiquitinated (represented as ‘Ub’) cargo and traffic the cargo to the developing autophagic membrane.
Figure 2.
Figure 2.
Degradative events in autophagy. Autophagosome degradation centers around the fusion of the lysosome with the autophagosome. The pool of PtdIns3P surrounding the autophagosome recruits RAB7A. RAB7A facilitates binding of the autophagosome to the HOPS complex on the lysosome, and PLEKHM1 mediates this binding. As the membranes converge, a SNARE-mediated fusion event occurs between VAMP7 on the lysosome and STX17 on the autophagosome, with SNAP29 being recruited and acting as a Qab SNARE. This allows for fusion of the autophagosome and lysosome membranes and the degradation of autophagosome content.
Figure 3.
Figure 3.
Markers of degradative and secretory autophagosomes. Trafficking of the autophagosome depends on the proteins decorating the outer membrane. Both degradative and secretory routes are labeled with LC3. STX17 directs fusion of the degradative autophagosome with the lysosome. SEC22B and TRIM16 direct an autophagosome for secretion.
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References

    1. Takeshige K, Baba M, Tsuboi S, et al. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol. 1992;119:301–311. - PMC - PubMed
    1. Schweers RL, Zhang J, Randall MS, et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci U S A. 2007;104:19500–19505. - PMC - PubMed
    1. Kraya AA, Piao S, Xu X, et al. Identification of secreted proteins that reflect autophagy dynamics within tumor cells. Autophagy. 2015;11:60–74. - PMC - PubMed
    1. Kimura T, Jia J, Kumar S, et al. Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J. 2017;36:42–60. - PMC - PubMed
    1. Jackson WT, Giddings TH Jr., Taylor MP, et al. Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol. 2005;3:e156. - PMC - PubMed

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