Role of the mammalian ATG8/LC3 family in autophagy: differential and compensatory roles in the spatiotemporal regulation of autophagy

Lee, You-Kyung;Lee, Jin-A

  • Received : 2016.05.10
  • Accepted : 2016.06.29
  • Published : 2016.08.31


Autophagy, an evolutionarily conserved cellular degradation pathway of the lysosome, is associated with many physiological and pathological processes. The hallmark of autophagy is the formation of the autophagosome that engulfs and degrades cytosolic components via its fusion with the lysosome, in either a selective or a non-selective manner. Autophagy is tightly regulated by proteins encoded by autophagy-related (atg) genes. Among these proteins, ATG8/LC3 is essential for autophagosome biogenesis/maturation and it also functions as an adaptor protein for selective autophagy. In mammalian cells, several homologs of yeast Atg8 such as MAP1LC3, GABARAP, and GABARAPL 1/2 have been identified. However, the biological relevance of this gene diversity in higher eukaryotes, and their specific roles, are largely unknown. In this review, we describe the mammalian ATG8/LC3 family and discuss recent advancements in understanding their roles in the autophagic process.




  1. Klionsky DJ and Codogno P (2013) The mechanism and physiological function of macroautophagy. J Innate Immun 5, 427-433
  2. Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8, 931-937
  3. Schneider JL and Cuervo AM (2014) Autophagy and human disease: emerging themes. Curr Opin Genet Dev 26, 16-23
  4. Ktistakis NT and Tooze SA (2016) Digesting the Expanding Mechanisms of Autophagy. Trends Cell Biol 26, 624-635
  5. Ponpuak M, Mandell MA, Kimura T, Chauhan S, Cleyrat C and Deretic V (2015) Secretory autophagy. Curr Opin Cell Biol 35, 106-116
  6. Xie Z and Klionsky DJ (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9, 1102-1109
  7. Rogov V, Dotsch V, Johansen T and Kirkin V (2014) Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell 53, 167-178
  8. Martinez J, Almendinger J, Oberst A et al (2011) Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc Natl Acad Sci U S A 108, 17396-17401
  9. Slobodkin MR and Elazar Z (2013) The Atg8 family: multifunctional ubiquitin-like key regulators of autophagy. Essays Biochem 55, 51-64
  10. Xin Y, Yu L, Chen Z et al (2001) Cloning, expression patterns, and chromosome localization of three human and two mouse homologues of GABA(A) receptor-associated protein. Genomics 74, 408-413
  11. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y and Yoshimori T (2004) LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci 117, 2805-2812
  12. Stadel D, Millarte V, Tillmann KD et al (2015) TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export. Mol Cell 60, 89-104
  13. Coyle JE and Nikolov DB (2003) GABARAP: lessons for synaptogenesis. Neuroscientist 9, 205-216
  14. Chen ZW and Olsen RW (2007) GABAA receptor associated proteins: a key factor regulating GABAA receptor function. J Neurochem 100, 279-294
  15. Engedal N and Seglen PO (2016) Autophagy of cytoplasmic bulk cargo does not require LC3. Autophagy 12, 439-441
  16. Pellerin I, Vuillermoz C, Jouvenot M, Ordener C, Royez M and Adessi GL (1993) Identification and characterization of an early estrogen-regulated RNA in cultured guinea-pig endometrial cells. Mol Cell Endocrinol 90, R17-21
  17. Le Grand JN, Chakrama FZ, Seguin-Py S et al (2011) GABARAPL1 (GEC1): original or copycat? Autophagy 7, 1098-1107
  18. Sagiv Y, Legesse-Miller A, Porat A and Elazar Z (2000) GATE-16, a membrane transport modulator, interacts with NSF and the Golgi v-SNARE GOS-28. EMBO J 19, 1494-1504
  19. Tolle F, Risold PY, Mansuy-Schlick V et al (2008) Specific regional distribution of gec1 mRNAs in adult rat central nervous system. Brain Res 1210, 103-115
  20. Feng Y, Yao Z and Klionsky DJ (2015) How to control self-digestion: transcriptional, post-transcriptional, and post-translational regulation of autophagy. Trends Cell Biol 25, 354-363
  21. Sugawara K, Suzuki NN, Fujioka Y, Mizushima N, Ohsumi Y and Inagaki F (2004) The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8. Genes Cells 9, 611-618
  22. Birgisdottir AB, Lamark T and Johansen T (2013) The LIR motif - crucial for selective autophagy. J Cell Sci 126, 3237-3247
  23. Huang R, Xu Y, Wan W et al (2015) Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol Cell 57, 456-466
  24. Alemu EA, Lamark T, Torgersen KM et al (2012) ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J Biol Chem 287, 39275-39290
  25. Joachim J, Jefferies HB, Razi M et al (2015) Activation of ULK Kinase and Autophagy by GABARAP Trafficking from the Centrosome Is Regulated by WAC and GM130. Mol Cell 60, 899-913
  26. Colecchia D, Strambi A, Sanzone S et al (2012) MAPK15/ERK8 stimulates autophagy by interacting with LC3 and GABARAP proteins. Autophagy 8, 1724-1740
  27. Feng Y, He D, Yao Z and Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24, 24-41
  28. Fujita N, Hayashi-Nishino M, Fukumoto H et al (2008) An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol Biol Cell 19, 4651-4659
  29. Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V and Elazar Z (2010) LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J 29, 1792-1802
  30. Albanesi J, Wang H, Sun HQ, Levine B and Yin H (2015) GABARAP-mediated targeting of PI4K2A/PI4KIIalpha to autophagosomes regulates PtdIns4P-dependent autophagosome-lysosome fusion. Autophagy 11, 2127-2129
  31. McEwan DG, Popovic D, Gubas A et al (2015) PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol Cell 57, 39-54
  32. Pankiv S, Alemu EA, Brech A et al (2010) FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J Cell Biol 188, 253-269
  33. Popovic D, Akutsu M, Novak I, Harper JW, Behrends C and Dikic I (2012) Rab GTPase-activating proteins in autophagy: regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers. Mol Cell Biol 32, 1733-1744
  34. Wild P, McEwan DG and Dikic I (2014) The LC3 interactome at a glance. J Cell Sci 127, 3-9
  35. Kalvari I, Tsompanis S, Mulakkal NC et al (2014) iLIR: A web resource for prediction of Atg8-family interacting proteins. Autophagy 10, 913-925
  36. Lystad AH, Ichimura Y, Takagi K et al (2014) Structural determinants in GABARAP required for the selective binding and recruitment of ALFY to LC3B-positive structures. EMBO Rep 15, 557-565
  37. Ambivero CT, Cilenti L, Main S and Zervos AS (2014) Mulan E3 ubiquitin ligase interacts with multiple E2 conjugating enzymes and participates in mitophagy by recruiting GABARAP. Cell Signal 26, 2921-2929
  38. Gao C, Cao W, Bao L et al (2010) Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation. Nat Cell Biol 12, 781-790
  39. Kang YA, Sanalkumar R, O’Geen H et al (2012) Autophagy driven by a master regulator of hematopoiesis. Mol Cell Biol 32, 226-239
  40. Xiao J, Zhu X, He B et al (2011) MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-II. J Biomed Sci 18, 35
  41. Cherra SJ 3rd, Kulich SM, Uechi G et al (2010) Regulation of the autophagy protein LC3 by phosphorylation. J Cell Biol 190, 533-539
  42. Wilkinson DS, Jariwala JS, Anderson E et al (2015) Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Mol Cell 57, 55-68
  43. Lee IH and Finkel T (2009) Regulation of autophagy by the p300 acetyltransferase. J Biol Chem 284, 6322-6328
  44. Tanji K, Odagiri S, Maruyama A et al (2013) Alteration of autophagosomal proteins in the brain of multiple system atrophy. Neurobiol Dis 49, 190-198

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Grant : 국가과학자지원

Supported by : 서울대학교