Autophagy comprises several evolutionarily conserved mechanisms for uptake and transport of proteins and even cytoplasmic organelles to the lysosome for degradation. Although the importance of autophagy for cell homeostasis and survival has long been appreciated, our understanding of how autophagy is carried out at the molecular level has recently benefited from genetic studies that have revealed the functions of many of the participating proteins. The importance of autophagy for maintaining quality control on proteins and organelles is underscored by the fact that many diseases exhibit dysfunctional autophagic activities, for example neurodegenerative diseases. When cells undergoing stress leading to deoxyribonucleic acid damage, mitochondrial damage, and/or accumulation of damaged proteins are unable to induce a sufficient autophagic response, genetic instability ensues and such cells are prone to accumulate oncogenic mutations. Thus, autophagy is required for multiple roles in the prevention of human disease.

Key Concepts

  • Though a basal or constitutive level of autophagy is present in almost all cell types all the time for elimination of damaged proteins and even dysfunctional organelles, for example, mitochondria, autophagy can be strongly induced to compensate for nutritional imbalances or in response to stresses such as DNA damage.
  • Autophagy is carried out by a set of more than 30 proteins encoded by the Autophagy‐Related genes (ATGs), the functions of which have been dissected using genetic and biochemical approaches.
  • lncreasingly, it is becoming clear that proteins encoded by ATG genes carry out functions in cellular pathways independent of their roles in autophagy.
  • Autophagy is a process in which a cup‐shaped, double‐membrane phagophore develops from a region of or near modified endoplasmic reticulum and closes, either unselectively in bulk or selectively, around sequestered cytoplasmic cargos, finally fusing with a lysosome to deliver the contents for degradation.
  • Dysregulated autophagy contributes to many pathologic processes including cancer and neurodegenerative diseases.

Keywords: autophagy; ATG; Beclin 1; LC3; mTORC1; p62/SQSTM1; PI3K; ULK1/2

Figure 1. The pathway for major molecular steps in autophagy. Upon activation, a preautophagosomal structure on or near the ER (endoplasmic reticulum) is formed, generating the phagophore or isolation membrane in a stepwise process as different proteins associate and recruit other players. Whenever mTORC1 is inactivated, the initiation complex of ULK1/2, ATG13, ATG101 (here 101) and FIP200 associate and the kinase activity is activated at the nascent phagophore. Thereby, ATG14 is phosphorylated, recruiting the Beclin1 followed by the entire PI3K complex. The local production of PI 3‐P (shown as a cloud) recruits the phospholipid binding proteins (here only WIPI is shown) and initiates the ubiquitin‐like conjugation reactions that produce first ATG12‐ATG5–ATG16, which must associate first with the phagophore, before conjugation of LC3‐PE can occur. ATG12‐ATG5–ATG16 is present in small amounts very early, even before the PI3K is fully active. Note that the association of the PI3K complex and ATG12‐ATG5–ATG16 with the phagophore is transient, and also that LC3 on the cytoplasmic side of the mature autophagosome is also cleaved away from the membrane. P62 (here 62) associates with poly‐ubiquitinated protein aggregates, then binding LC3, allowing the phagophore to engulf other cytosolic elements and organelles, growing and finally closing, forming the autophagosome, which, in turn, fuses with endocytic vesicles forming the so‐called mature autophagosome or amphisome. Subsequently, it is transported centrally on microtubules by dynein, finally fusing with a lysosome. In the lysosome, the sequestered material is digested by lysosomal acid hydrolases (proteases and lipases).
Figure 2. Regulation of autophagy. The protein kinase complex, mTORC1, made up of the catalytic subunit, Target of Rapamycin (TOR), the Raptor regulatory/scaffold subunit and other proteins plays the central role in the signaling pathways involved in regulation of autophagy. The ULK1/2 kinase complex initiates autophagy when mTORC1 inactivation interrupts the inhibitory phosphorylation of ULK1/2. ULK1/2 phosphorylation targets include ATG13, FIP200 in the autophagy initiating complex, the ER‐associated protein ATG14 and Beclin 1. The latter recruit the remaining elements of the PI3K complex to the phagophore. This complex comprises the catalytic subunit Vps34, Vps15 and Beclin 1. However, Beclin1 availability is a major limitation, representing an important regulatory step, since it must be freed of its binding partners like to Bcl‐2 and Bcl‐XL, for example by Bcl‐2 phosphorylation (not shown). Thus, the requirement for Beclin 1 represents a cross‐talk between the core machineries regulating autophagy and apoptosis.


Amaya C, Fader CM and Colombo MI (2015) Autophagy and proteins involved in vesicular trafficking. FEBS Letters 589: 3343–3353.

Andrade RM, Wessendarp M, Gubbels MJ, Striepen B and Subauste CS (2006) CD40 induces macrophage anti‐Toxoplasma gondii activity triggering autophagy‐dependent fusion of pathogen‐containing vacuoles and lysosomes. Journal of Clinical Investigation 116: 2366–2377.

Belaid A, Ndiaye PD, Klionsky DJ, Hofman P and Mograbi B (2013) Signalphagy: scheduled signal termination by autophagy. Autophagy 9: 1629–1630.

Demetriades C, Doumpas N and Teleman AA (2014) Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell 156: 786–799.

Delgado MA and Deretic V (2009) Toll‐like receptors in control of immunological autophagy. Cell Death and Differentiation 16: 976–983.

Deretic V (2011) Autophagy in immunity and cell‐autonomous defense against intracellular microbes. Immunological Reviews 240: 92–104.

Ditch S and Paull TT (2012) The ATM protein kinase and cellular redox signaling: beyond the DNA damage response. Trends in Biochemical Sciences 37: 15–22.

Eisenberg‐Lerner A, Bialik S, Simon HU and Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross‐talk between them. Cell Death and Differentiation 16: 966–975.

Feng Z, Hu W, de Stanchina E, et al. (2007) The regulation of AMPK β1, TSC2 and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF‐1‐AKT‐mTOR pathways. Cancer Research 67: 3043–3053.

Galluzzi L, Vitale I, Abrams JM, et al. (2012) Molecular definitions of cell death subroutines. Recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death and Differentiation 19: 107–120.

Galluzzi L, Pietrocola F, Bravo‐San Pedro MB, et al. (2015) Autophagy in malignant transformation and cancer progression. EMBO Journal 34: 856–880.

Groehe RW, Xu D, Sharma K, et al. (2012) The autophagy‐senescence connection in chemotherapy: must tumor cells (self) eat before they sleep? Journal of Pharmacology and Experimental Therapeutics 343: 763–778.

Gutierrez MG, Munafo DB, Beron W and Colombo MI (2004a) Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. Journal of Cell Science 117: 2687–2697.

Gutierrez MG, Master SS, Singh SB, et al. (2004b) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119: 753–766.

Hamasaki M, Furuta N, Matsuda Am Nezu A, et al. (2013) Autophagosomes form at ER‐mitochondria contact sites. Nature 495: 389–393.

Huang J, Birmingham CL, Shahnazari S, et al. (2011) Antibacterial autophagy occurs at PtdIns(3)P‐enriched domains of the endoplasmic reticulum and requires Rab1 GTPase. Autophagy 7: 17–26.

Itakura E, Kishi‐Itakura C and Mizushima N (2012) The hairpin‐type tail‐anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151: 1256–1269.

Jager S, Bucci C, Tanida I, et al. (2004) Role of Rab7 in maturation of late autophagic vacuoles. Journal of Cell Science 117 (part 20): 4837–4848.

Jain N and Ganesh S (2016) Emerging nexus between RAB GTPases, autophagy and neurodegeneration. Autophagy 12: 900–904.

Jiang P, Nishimura T, Sakamaki Y, et al. (2014) The HOPS complex mediates autophagosome‐lysosome fusion through interaction with syntaxin 17. Molecular Biology of the Cell 25: 1327–1337.

Kimura S, Noda T and Yoshimori T (2008) Dynein‐dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Structure and Function 33: 109–122.

Kishi‐Itakura C, Koyama‐Honda I, Itakura E and Mizushima N (2014) Ulltrastructural analysis of autophagosome organization using mammalian autophagy‐deficient cells. Journal of Cell Science 127: 4089–4102.

Koyama‐Honda I, Itakura E, Fujiwara TK and Mizushima N (2013) Temporal analysis of recruitment of mammalian ATG proteins to the autophagosome formation site. Autophagy 9: 1491–1499.

Koyano F, Okatsu K, Kosako H, et al. (2014) Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510: 162–166.

Kroemer G, Mariño G and Levine B (2010) Autophagy and the integrated stress response. Cell 40: 280–293.

Lamb CA, Yoshimori T and Tooze SA (2013) The autophagosome: origins unknown, biogenesis complex. Nature Reviews Molecular Cell Biology 14: 759–774.

Laplante M and Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149: 274–293.

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

Levine B, Mizushima N and Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469: 323–335.

Liang XH, Jackson S, Seaman M, et al. (1999) Induction of autophagy and inhibition of tumorigenesis by Beclin 1. Nature 402: 672–676.

Lin L and Baehrecke EH (2015) Autophagy, cell death and cancer. Molecular and Cellular Oncology 2 (3): e985913. DOI: 10.4161/23723556.2014.985913.

Liu H, He Z, von Rutte T, et al. (2013) Down‐regulation of autophagy‐related protein 5 (ATG5) contributes to the pathogenesis of early stage cutaneous melanoma. Science Translational Medicine 5: 202ra123.

Loi M, Müller A, Steinbach K, et al. (2016) Macroautophagy proteins control MHC Class I levels on dendritic cells and shape anti‐viral CD8+ T cell responses. Cell Reports 15: 1076–1087.

López de Armentia MM, Amaya C and Colombo MI (2016) Rab GTPases and the autophagy pathway: bacterial targets for a suitable biogenesis and trafficking of their own vacuoles. Cells 5: Article no. 11. DOI: 10.3390/cells5010011.

Maiuri MC, Le Toumelin G, Criollo A, et al. (2007) Functional and physical interaction between Bcl‐X(L) and a BH3‐like domain on Beclin1. EMBO Journal 26: 2527–2539.

Mathew R, Karp CM, Beaudoin B, et al. (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137: 1062–1075.

Matsunaga K, Morita E, Saitoh T, et al. (2010) Autophagy requires endoplasmic reticulum targeting of the PI3‐kinase complex via Atg 14L. Journal of Cell Biology 190: 511–521.

Militello RD and Colombo MI (2011) A membrane is born: origin of the autophagosomal compartment. Current Molecular Medicine 11: 197–203.

Mizushima N and Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147: 728–741.

Ogawa M, Mimuro H, Yoshikawa Y, Ashida H and Sasakawa C (2011) Manipulation of autophagy by bacteria for their own benefit. Microbiology and Immunology 55: 459–471.

Orsi A, Razi M, Dooley HC, et al. (2012) Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Molecular Biology of the Cell 23: 1860–1873.

Pietrocola F, Izzo V, Niso‐Santano M, et al. (2013) Regulation of autophagy by stress‐responsive transcription factors. Seminars in Cancer Biology 23: 310–322.

Rubinsztein DC, Gestwicki JE, Murphy LO and Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nature Reviews Drug Discovery 6: 304–312.

Russell RC, Yuan HX and Guan KL (2014) Autophagy regulation by nutrient signaling. Cell Research 24: 42–57.

Scherz‐Shouval R and Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends in Biochemical Sciences 36: 30–38.

Seglen PO and Gordon PB (1982) 3‐methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proceedings of the National Academy of Sciences of the United States of America 79: 1889–1892.

Szatmari Z and Sass M (2014) The autophagic roles of Rab small GTPases and their upstream regulators: a review. Autophagy 10: 1154–1166.

Ward C, Martinez‐Lopez N, Otten EG, et al. (2016) Autophagy, lippophagy and lysosomal storage disorders. Biochimica et Biophysica Acta 1861: 269–284.

Williams A, Jahreiss L, Sarkar S, et al. (2006) Aggregate‐prone proteins are cleared from the cytosol by autophagy: therapeutic implications. Current Topics in Developmental Biology 76: 89–101.

Winslow AR, Chen CW, Corrochano S, et al. (2010) Alpha‐synuclein impairs macroautophagy: implications for Parkinson disease. Journal of Cell Biology 190: 1023–1037.

Wong YC and Holzbaur ELF (2014a) Optineurin is an autophagy receptor for damaged mitochondria in parkin‐mediated mitophagy that is disrupted in an ALS‐linked mutation. Proceedings of the National Academy of Sciences of the United States of America 111: E4439–E4448.

Wong YC and Holzbaur ELF (2014b) The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. Journal of Neuroscience 34: 1293–1305.

Yang Z and Klionsky DJ (2010) Mammalian autophagy: core machinery and signaling regulation. Current Opinion in Cell Biology 22: 124–131.

Youle RJ and Narendra DP (2011) Mechanisms of mitophagy. Nature Reviews 12: 9–14.

Yousefi S, Perozzo R, Schmid I, et al. (2006) Calpain‐mediated cleavage of Atg5 switches autophagy to apoptosis. Nature Cell Biology 8: 1124–1132.

Yu WH, Cuervo AM, Kumar A, et al. (2005) Mactroautophagy ‐ a novel Beta‐amyloid peptide generating pathway activated in Alzheimer's disease. Journal of Cell Biology 171: 87–98.

Yue Z, Jin S, Yang C, Levine AJ and Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America 100: 15077–15082.

Zaffagnini G and Martens S (2016) Mechanisms of selective autophagy. Journal of Molecular Biology 428: 1714–17724.

Zoppino FC, Militello RD, Slavin I, Alvarez C and Colombo MI (2010) Autophagosome formation depends on the small GTPase Rab1 and functional ER exit sites. Traffic 11: 1246–1261.

Further Reading

Eisenberg‐Lerner A, Bialik S, Simon HU and Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross‐talk between them. Cell Death and Differentiation 16: 966–975.

Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nature Reviews. Molecular Cell Biology 8: 931–937.

Kroemer G, Mariño G and Levine B (2010) Autophagy and the integrated stress response. Cell 40: 280–293.

Levine B and Deretic V (2007) Unveiling the roles of autophagy in innate and adaptive immunity. Nature Reviews. Immunology 7: 767–777.

Ohsumi Y and Mizushima N (2004) Two ubiquitin‐like conjugation system essential for autophagy. Seminars in Cell and Developmental Biology 1: 231–236.

Ricoult SJH and Manning BD (2013) The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Reports 14: 242–251.

Yousefi S and Simon HU (2009) Autophagy in cells of the blood. Biochimica et Biophysica Acta 1793: 1461–1464.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Simon, Hans‐Uwe, Friis, Robert, and Colombo, María I(Mar 2017) Autophagy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021581.pub2]