Abstract
Autophagy maintains cell, tissue and organism homeostasis through degradation. Complex post-translational modulation of the Atg (autophagy-related) proteins adds additional entry points for crosstalk with other cellular processes and helps define cell-type-specific regulations of autophagy. Beyond the simplistic view of a process exclusively dedicated to the turnover of cellular components, recent data have uncovered unexpected functions for autophagy and the autophagy-related genes, such as regulation of metabolism, membrane transport and modulation of host defenses — indicating the novel frontiers lying ahead.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
01 July 2013
In the print version of this Review, Table 2 was mistakenly omitted. It appears correctly in the HTML and PDF versions.
References
Yang, Z. & Klionsky, D. J. Eaten alive: a history of macroautophagy. Nat. Cell Biol. 12, 814–822 (2010).
Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011).
Rubinsztein, D. C., Shpilka, T. & Elazar, Z. Mechanisms of autophagosome biogenesis. Curr. Biol. 22, R29–34 (2012).
Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).
Hayashi-Nishino, M. et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11, 1433–1437 (2009).
Yla-Anttila, P., Vihinen, H., Jokitalo, E. & Eskelinen, E. L. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5, 1180–1185 (2009).
Hailey, D. W. et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141, 656–667 (2010).
Deretic, V. & Levine, B. Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5, 527–549 (2009).
Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).
Reggiori, F., Komatsu, M., Finley, K. & Simonsen, A. Autophagy: more than a nonselective pathway. Int. J. Cell Biol. 2012, 219625 (2012).
Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263 (2012).
Johansen, T. & Lamark, T. Selective autophagy mediated by autophagic adapter proteins. Autophagy 7, 279–296 (2011).
Noda, N. N., Ohsumi, Y. & Inagaki, F. Atg8-family interacting motif crucial for selective autophagy. FEBS Lett. 584, 1379–1385 (2010).
Lynch-Day, M. A. et al. Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy. Proc. Natl Acad. Sci. USA 107, 7811–7816 (2010).
Motley, A. M., Nuttall, J. M. & Hettema, E. H. Pex3-anchored Atg36 tags peroxisomes for degradation in Saccharomyces cerevisiae. EMBO J. 31, 2852–2868 (2012).
Kanki, T., Wang, K., Cao, Y., Baba, M. & Klionsky, D. J. Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev. Cell 17, 98–109 (2009).
Okamoto, K., Kondo-Okamoto, N. & Ohsumi, Y. Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev. Cell 17, 87–97 (2009).
Shaid, S., Brandts, C. H., Serve, H. & Dikic, I. Ubiquitination and selective autophagy. Cell Death Differ. 20, 21–30 (2013).
Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).
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).
Liu, L. et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat. Cell Biol. 14, 177–185 (2012).
Watson, R. O., Manzanillo, P. S. & Cox, J. S. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150, 803–815 (2012).
Orvedahl, A. et al. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480, 113–117 (2011).
Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).
Meijer, A. J. & Codogno, P. Autophagy: regulation and role in disease. Crit. Rev. Clin. Lab. Sci. 46, 210–240 (2009).
McEwan, D. G. & Dikic, I. The Three Musketeers of Autophagy: phosphorylation, ubiquitylation and acetylation. Trends Cell Biol. 21, 195–201 (2011).
Stephan, J. S., Yeh, Y. Y., Ramachandran, V., Deminoff, S. J. & Herman, P. K. The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc. Natl Acad. Sci. USA 106, 17049–17054 (2009).
Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).
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).
Wei, Y., Pattingre, S., Sinha, S., Bassik, M. & Levine, B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol. Cell 30, 678–688 (2008).
Zalckvar, E. et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-X(L) and induction of autophagy. EMBO Rep. 30, 30 (2009).
Wang, R. C. et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956–959 (2012).
Kim, J. et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152, 290–303 (2013).
Cherra, S. J., 3rd. et al. Regulation of the autophagy protein LC3 by phosphorylation. J. Cell Biol. 190, 533–539 (2010).
Matsumoto, G., Wada, K., Okuno, M., Kurosawa, M. & Nukina, N. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol. Cell 44, 279–289 (2011).
Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233 (2011).
Radoshevich, L. et al. ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell 142, 590–600 (2010).
Morselli, E. et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615–629 (2011).
Lee, I. H. et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl Acad. Sci. USA 105, 3374–3379 (2008).
Lee, I. H. & Finkel, T. Regulation of autophagy by the p300 acetyltransferase. J. Biol. Chem. 284, 6322–6328 (2009).
Yi, C. et al. Function and molecular mechanism of acetylation in autophagy regulation. Science 336, 474–477 (2012).
Lin, S. Y. et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336, 477–481 (2012).
Hamai, A. & Codogno, P. New targets for acetylation in autophagy. Sci. Signal. 5, pe29 (2012).
Duran, J. M., Anjard, C., Stefan, C., Loomis, W. F. & Malhotra, V. Unconventional secretion of Acb1 is mediated by autophagosomes. J. Cell Biol. 188, 527–536 (2010).
Manjithaya, R., Anjard, C., Loomis, W. F. & Subramani, S. Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation. J. Cell Biol. 188, 537–546 (2010).
Dupont, N. et al. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β. Embo J 30, 4701–4711 (2011).
Bruns, C., McCaffery, J. M., Curwin, A. J., Duran, J. M. & Malhotra, V. Biogenesis of a novel compartment for autophagosome-mediated unconventional protein secretion. J. Cell Biol. 195, 979–992 (2011).
Jackson, W. T. et al. Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol. 3, e156 (2005).
Griffiths, R. E. et al. Maturing reticulocytes internalize plasma membrane in glycophorin A-containing vesicles that fuse with autophagosomes before exocytosis. Blood 119, 6296–6306 (2012).
Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011).
Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334, 678–683 (2011).
Deretic, V., Jiang, S. & Dupont, N. Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation. Trends Cell Biol. 22, 397–406 (2012).
DeSelm, C. J. et al. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev. Cell 21, 966–974 (2011).
Sanjuan, M. A. et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253–1257 (2007).
Nakatogawa, H., Ichimura, Y. & Ohsumi, Y. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130, 165–178 (2007).
Weidberg, H. et al. LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev. Cell 20, 444–454 (2011).
Monastyrska, I., Rieter, E., Klionsky, D. J. & Reggiori, F. Multiple roles of the cytoskeleton in autophagy. Biol. Rev. Camb. Philos. Soc. 84, 431–448 (2009).
Mellén, M. A., de la Rosa, E. J. & Boya, P. The autophagic machinery is necessary for removal of cell corpses from the developing retinal neuroepithelium. Cell Death Differ. 15, 1279–1290 (2008).
Qu, X. et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931–946 (2007).
Suzuki, S. W., Onodera, J. & Ohsumi, Y. Starvation induced cell death in autophagy-defective yeast mutants is caused by mitochondria dysfunction. PloS One 6, e17412 (2011).
Ezaki, J. et al. Liver autophagy contributes to the maintenance of blood glucose and amino acid levels. Autophagy 7, 727–736 (2011).
Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).
White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer 12, 401–410 (2012).
Lunt, S. Y. & Vander Heiden, M. G. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441–464 (2011).
Porporato, P. E., Dhup, S., Dadhich, R. K., Copetti, T. & Sonveaux, P. Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol. 2, 49 (2011).
Semenza, G. L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56 (2010).
Frezza, C. et al. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PloS One 6, e24411 (2011).
Chang, Y. et al. miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology 143, 177–187 (2012).
Ermak, G. et al. Chronic expression of RCAN1-1L protein induces mitochondrial autophagy and metabolic shift from oxidative phosphorylation to glycolysis in neuronal cells. J. Biol. Chem. 287, 14088–14098 (2012).
Pavlides, S. et al. Warburg meets autophagy: cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis. Antioxid. Redox Signal. 16, 1264–1284 (2012).
Capparelli, C. et al. Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle 11, 2285–2302 (2012).
Eng, C. H. & Abraham, R. T. Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy 6, 968–970 (2010).
Di Malta, C., Fryer, J. D., Settembre, C. & Ballabio, A. Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. Proc. Natl Acad. Sci. USA 109, E2334–2342 (2012).
Behrends, C., Sowa, M. E., Gygi, S. P. & Harper, J. W. Network organization of the human autophagy system. Nature 466, 68–76 (2010).
Subramani, S. & Malhotra, V. Non-autophagic roles of autophagy-related proteins. EMBO Rep. 14, 143–151 (2013).
Jounai, N. et al. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc. Natl Acad. Sci. USA 104, 14050–14055 (2007).
Hwang, S. et al. Nondegradative role of Atg5-Atg12/Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. Cell Host Microbe 11, 397–409 (2012).
Zhao, Z. et al. Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe 4, 458–469 (2008).
Starr, T. et al. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe 11, 33–45 (2012).
Cali', T., Galli, C., Olivari, S. & Molinari, M. Segregation and rapid turnover of EDEM1 by an autophagy-like mechanism modulates standard ERAD and folding activities. Biochem. Biophys. Res. Commun. 371, 405–410 (2008).
Reggiori, F. et al. Coronaviruses hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 7, 500–508 (2010).
Rubinstein, A. D., Eisenstein, M., Ber, Y., Bialik, S. & Kimchi, A. The autophagy protein Atg12 associates with anti-apoptotic Bcl-2 family members to promote mitochondrial apoptosis. Mol. Cell 44, 698–709 (2011).
Yousefi, S. et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat. Cell Biol. 8, 1124–1132 (2006).
Luo, S. & Rubinsztein, D. C. Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ. 17, 268–277 (2010).
Wirawan, E. et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 1, e18 (2010).
Galluzzi, L., Kepp, O., Trojel-Hansen, C. & Kroemer, G. Non-apoptotic functions of apoptosis-regulatory proteins. EMBO Rep. 13, 322–330 (2012).
Lee, J. Y. et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. Embo J. 29, 969–980 (2010).
Suzuki, K., Kubota, Y., Sekito, T. & Ohsumi, Y. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12, 209–218 (2007).
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).
Kageyama, S. et al. The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella. Mol. Biol. Cell 22, 2290–2300 (2011).
Codogno, P., Mehrpour, M. & Proikas-Cezanne, T. Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat. Rev. Mol. Cell Biol. 13, 7–12 (2011).
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).
Florey, O., Kim, S. E., Sandoval, C. P., Haynes, C. M. & Overholtzer, M. Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nat. Cell Biol. 13, 1335–1343 (2011).
Martinez, J. et al. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc. Natl Acad. Sci. USA 108, 17396–17401 (2011).
Acknowledgements
P.B. is supported by the SAF-2009-08086 and SAF-2012-36079 grants. F.R. is supported by the ECHO (700.59.003), ALW Open Program (821.02.017 and 822.02.014), DFG-NWO cooperation (DN82-303) and ZonMW VICI (016.130.606) grants. P.C. is supported by INSERM and grants from ANR and INCa.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Boya, P., Reggiori, F. & Codogno, P. Emerging regulation and functions of autophagy. Nat Cell Biol 15, 713–720 (2013). https://doi.org/10.1038/ncb2788
Published:
Issue date:
DOI: https://doi.org/10.1038/ncb2788
This article is cited by
-
Arginyltransferase 1 modulates p62-driven autophagy via mTORC1/AMPk signaling
Cell Communication and Signaling (2024)
-
Protective effect of hygrolansamycin C against corticosterone-induced toxicity and oxidative stress-mediated via autophagy and the MAPK signaling pathway
Pharmacological Reports (2024)
-
Ivermectin induces nonprotective autophagy by downregulating PAK1 and apoptosis in lung adenocarcinoma cells
Cancer Chemotherapy and Pharmacology (2024)
-
Lysosomal cation channel TRPML1 suppression sensitizes acute myeloid leukemia cells to chemotherapeutics by inhibiting autophagy
Molecular and Cellular Biochemistry (2024)
-
Efficacy of zinc oxide and copper oxide nanoparticles on virulence genes of avian pathogenic E. coli (APEC) in broilers
BMC Veterinary Research (2023)
