Home LiteratureArticle Details
PMID: 21867568 Published · epublish English Journal Article Review

Atg8: an autophagy-related ubiquitin-like protein family.

Genome biology ·Vol. 12 ·No. 7 ·2011-07-27 ·Pages 226

Shpilka T, Weidberg H, Pietrokovski S, Elazar Z

Abstract

Autophagy-related (Atg) proteins are eukaryotic factors participating in various stages of the autophagic process. Thus far 34 Atgs have been identified in yeast, including the key autophagic protein Atg8. The Atg8 gene family encodes ubiquitin-like proteins that share a similar structure consisting of two amino-terminal α helices and a ubiquitin-like core. Atg8 family members are expressed in various tissues, where they participate in multiple cellular processes, such as intracellular membrane trafficking and autophagy. Their role in autophagy has been intensively studied. Atg8 proteins undergo a unique ubiquitin-like conjugation to phosphatidylethanolamine on the autophagic membrane, a process essential for autophagosome formation. Whereas yeast has a single Atg8 gene, many other eukaryotes contain multiple Atg8 orthologs. Atg8 genes of multicellular animals can be divided, by sequence similarities, into three subfamilies: microtubule-associated protein 1 light chain 3 (MAP1LC3 or LC3), γ-aminobutyric acid receptor-associated protein (GABARAP) and Golgi-associated ATPase enhancer of 16 kDa (GATE-16), which are present in sponges, cnidarians (such as sea anemones, corals and hydras) and bilateral animals. Although genes from all three subfamilies are found in vertebrates, some invertebrate lineages have lost the genes from one or two subfamilies. The amino terminus of Atg8 proteins varies between the subfamilies and has a regulatory role in their various functions. Here we discuss the evolution of Atg8 proteins and summarize the current view of their function in intracellular trafficking and autophagy from a structural perspective.

MeSH Terms
Animals Autophagy Evolution, Molecular Humans Protein Transport Ubiquitins/chemistry,genetics,physiology
Chemicals
Ubiquitins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Shpilka Tomer
Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Weidberg Hilla
Pietrokovski Shmuel
Elazar Zvulun
References (113)
113 references, click to expand
  1. Atg8 controls phagophore expansion during autophagosome formation.
    Mol Biol Cell. 2008 Aug;19(8):3290-8 PMID: 18508918
  2. The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice.
    Mol Biol Cell. 2008 Nov;19(11):4762-75 PMID: 18768753
  3. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation.
    J Cell Sci. 2004 Jun 1;117(Pt 13):2805-12 PMID: 15169837
  4. Selective autophagy: ubiquitin-mediated recognition and beyond.
    Nat Cell Biol. 2010 Sep;12(9):836-41 PMID: 20811356
  5. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy.
    J Biol Chem. 2007 Dec 28;282(52):37298-302 PMID: 17986448
  6. Structure of GATE-16, membrane transport modulator and mammalian ortholog of autophagocytosis factor Aut7p.
    J Biol Chem. 2000 Aug 18;275(33):25445-50 PMID: 10856287
  7. GABA(A)-receptor-associated protein links GABA(A) receptors and the cytoskeleton.
    Nature. 1999 Jan 7;397(6714):69-72 PMID: 9892355
  8. Formation process of autophagosome is traced with Apg8/Aut7p in yeast.
    J Cell Biol. 1999 Oct 18;147(2):435-46 PMID: 10525546
  9. A phylogenomic investigation into the origin of metazoa.
    Mol Biol Evol. 2008 Apr;25(4):664-72 PMID: 18184723
  10. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates.
    Mol Cell. 2009 Feb 27;33(4):505-16 PMID: 19250911
  11. Current knowledge of the pre-autophagosomal structure (PAS).
    FEBS Lett. 2010 Apr 2;584(7):1280-6 PMID: 20138172
  12. Sequential SNARE disassembly and GATE-16-GOS-28 complex assembly mediated by distinct NSF activities drives Golgi membrane fusion.
    J Cell Biol. 2002 Jun 24;157(7):1161-73 PMID: 12070132
  13. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation.
    Nat Cell Biol. 2009 Dec;11(12):1433-7 PMID: 19898463
  14. The Pfam protein families database.
    Nucleic Acids Res. 2010 Jan;38(Database issue):D211-22 PMID: 19920124
  15. FoxO transcription factors promote autophagy in cardiomyocytes.
    J Biol Chem. 2009 Oct 9;284(41):28319-28331 PMID: 19696026
  16. The gamma-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics.
    Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11557-62 PMID: 10984509
  17. PX-RICS mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex.
    Genes Dev. 2008 May 1;22(9):1244-56 PMID: 18451111
  18. Expression of gec1/GABARAPL1 versus GABARAP mRNAs in human: predominance of gec1/GABARAPL1 in the central nervous system.
    Brain Res Mol Brain Res. 2003 Nov 26;119(2):216-9 PMID: 14625090
  19. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease.
    J Cell Biol. 2007 Nov 5;179(3):485-500 PMID: 17984323
  20. Atg8 regulates vacuolar membrane dynamics in a lipidation-independent manner in Pichia pastoris.
    J Cell Sci. 2010 Dec 1;123(Pt 23):4107-16 PMID: 21045113
  21. The Cvt pathway as a model for selective autophagy.
    FEBS Lett. 2010 Apr 2;584(7):1359-66 PMID: 20146925
  22. CDD: a Conserved Domain Database for the functional annotation of proteins.
    Nucleic Acids Res. 2011 Jan;39(Database issue):D225-9 PMID: 21109532
  23. GABARAPL1 (GEC1) associates with autophagic vesicles.
    Autophagy. 2010 May;6(4):495-505 PMID: 20404487
  24. GATE-16, a membrane transport modulator, interacts with NSF and the Golgi v-SNARE GOS-28.
    EMBO J. 2000 Apr 3;19(7):1494-504 PMID: 10747018
  25. Regulation of the autophagy protein LC3 by phosphorylation.
    J Cell Biol. 2010 Aug 23;190(4):533-9 PMID: 20713600
  26. Cytoplasm-to-vacuole targeting and autophagy employ the same machinery to deliver proteins to the yeast vacuole.
    Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12304-8 PMID: 8901576
  27. The genome sequence of Schizosaccharomyces pombe.
    Nature. 2002 Feb 21;415(6874):871-80 PMID: 11859360
  28. Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates.
    J Biol Chem. 2011 Mar 4;286(9):7327-38 PMID: 21177865
  29. A ubiquitin-like system mediates protein lipidation.
    Nature. 2000 Nov 23;408(6811):488-92 PMID: 11100732
  30. The COOH terminus of GATE-16, an intra-Golgi transport modulator, is cleaved by the human cysteine protease HsApg4A.
    J Biol Chem. 2003 Apr 18;278(16):14053-8 PMID: 12473658
  31. The nuclear cofactor DOR regulates autophagy in mammalian and Drosophila cells.
    EMBO Rep. 2010 Jan;11(1):37-44 PMID: 20010805
  32. The itinerary of a vesicle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways.
    J Biol Chem. 2000 Feb 25;275(8):5845-51 PMID: 10681575
  33. The TP53INP2 protein is required for autophagy in mammalian cells.
    Mol Biol Cell. 2009 Feb;20(3):870-81 PMID: 19056683
  34. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway.
    J Cell Biol. 1995 Nov;131(3):591-602 PMID: 7593182
  35. Isolation and characterization of a novel low molecular weight protein involved in intra-Golgi traffic.
    J Biol Chem. 1998 Jan 30;273(5):3105-9 PMID: 9446628
  36. Membrane recruitment of Aut7p in the autophagy and cytoplasm to vacuole targeting pathways requires Aut1p, Aut2p, and the autophagy conjugation complex.
    J Cell Biol. 2001 Jan 8;152(1):51-64 PMID: 11149920
  37. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy.
    Mol Cell. 2010 Apr 23;38(2):265-79 PMID: 20417604
  38. LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: caution in the interpretation of LC3 localization.
    Autophagy. 2007 Jul-Aug;3(4):323-8 PMID: 17387262
  39. AUT1, a gene essential for autophagocytosis in the yeast Saccharomyces cerevisiae.
    J Bacteriol. 1997 Feb;179(4):1068-76 PMID: 9023185
  40. Induced expressions of Rab24 GTPase and LC3 in nerve-injured motor neurons.
    Biochem Biophys Res Commun. 2005 Dec 2;337(4):1206-13 PMID: 16236257
  41. Dissection of autophagosome biogenesis into distinct nucleation and expansion steps.
    J Cell Biol. 2000 Nov 27;151(5):1025-34 PMID: 11086004
  42. The N-terminus and Phe52 residue of LC3 recruit p62/SQSTM1 into autophagosomes.
    J Cell Sci. 2008 Aug 15;121(Pt 16):2685-95 PMID: 18653543
  43. Two newly identified sites in the ubiquitin-like protein Atg8 are essential for autophagy.
    EMBO Rep. 2006 Jun;7(6):635-42 PMID: 16680092
  44. GEC1, a protein related to GABARAP, interacts with tubulin and GABA(A) receptor.
    Biochem Biophys Res Commun. 2004 Dec 10;325(2):639-48 PMID: 15530441
  45. Regulation of autophagy by the p300 acetyltransferase.
    J Biol Chem. 2009 Mar 6;284(10):6322-8 PMID: 19124466
  46. Insights into social insects from the genome of the honeybee Apis mellifera.
    Nature. 2006 Oct 26;443(7114):931-49 PMID: 17073008
  47. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.
    Science. 2011 Jul 8;333(6039):228-33 PMID: 21617041
  48. Effects of C-terminal modifications of GEC1 protein and gamma-aminobutyric acid type A (GABA(A)) receptor-associated protein (GABARAP), two microtubule-associated proteins, on kappa opioid receptor expression.
    J Biol Chem. 2011 Apr 29;286(17):15106-15 PMID: 21388957
  49. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion.
    Cell. 2007 Jul 13;130(1):165-78 PMID: 17632063
  50. In vivo and in vitro reconstitution of Atg8 conjugation essential for autophagy.
    J Biol Chem. 2004 Sep 24;279(39):40584-92 PMID: 15277523
  51. The subcellular distribution of GABARAP and its ability to interact with NSF suggest a role for this protein in the intracellular transport of GABA(A) receptors.
    Mol Cell Neurosci. 2001 Jul;18(1):13-25 PMID: 11461150
  52. Human light chain 3/MAP1LC3B is cleaved at its carboxyl-terminal Met121 to expose Gly120 for lipidation and targeting to autophagosomal membranes.
    J Biol Chem. 2004 Nov 12;279(46):47704-10 PMID: 15355958
  53. A single protease, Apg4B, is specific for the autophagy-related ubiquitin-like proteins GATE-16, MAP1-LC3, GABARAP, and Apg8L.
    J Biol Chem. 2003 Dec 19;278(51):51841-50 PMID: 14530254
  54. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.
    Cell Metab. 2007 Dec;6(6):472-83 PMID: 18054316
  55. GABAA receptor-associated protein traffics GABAA receptors to the plasma membrane in neurons.
    J Neurosci. 2004 Dec 15;24(50):11429-38 PMID: 15601949
  56. LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis.
    Dev Cell. 2011 Apr 19;20(4):444-54 PMID: 21497758
  57. Structure of GABARAP in two conformations: implications for GABA(A) receptor localization and tubulin binding.
    Neuron. 2002 Jan 3;33(1):63-74 PMID: 11779480
  58. Structural basis of target recognition by Atg8/LC3 during selective autophagy.
    Genes Cells. 2008 Dec;13(12):1211-8 PMID: 19021777
  59. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.
    J Biol Chem. 2007 Aug 17;282(33):24131-45 PMID: 17580304
  60. E2F1 regulates autophagy and the transcription of autophagy genes.
    Oncogene. 2008 Aug 14;27(35):4860-4 PMID: 18408756
  61. Adaptation of Hansenula polymorpha to methanol: a transcriptome analysis.
    BMC Genomics. 2010 Jan 04;11:1 PMID: 20044946
  62. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death.
    J Cell Biol. 2005 Nov 21;171(4):603-14 PMID: 16286508
  63. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis.
    EMBO J. 2010 Jun 2;29(11):1792-802 PMID: 20418806
  64. Solution structure of Atg8 reveals conformational polymorphism of the N-terminal domain.
    Biochem Biophys Res Commun. 2010 May 7;395(3):426-31 PMID: 20382112
  65. C-terminal modification is required for GABARAP-mediated GABA(A) receptor trafficking.
    J Neurosci. 2007 Jun 20;27(25):6655-63 PMID: 17581952
  66. FoxO3 controls autophagy in skeletal muscle in vivo.
    Cell Metab. 2007 Dec;6(6):458-71 PMID: 18054315
  67. Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism.
    J Biol Chem. 2010 Nov 5;285(45):34960-71 PMID: 20810658
  68. Nix is a selective autophagy receptor for mitochondrial clearance.
    EMBO Rep. 2010 Jan;11(1):45-51 PMID: 20010802
  69. Molecular characterization of light chain 3. A microtubule binding subunit of MAP1A and MAP1B.
    J Biol Chem. 1994 Apr 15;269(15):11492-7 PMID: 7908909
  70. An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure.
    Mol Biol Cell. 2008 Nov;19(11):4651-9 PMID: 18768752
  71. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker.
    Mol Biol Cell. 2004 Mar;15(3):1101-11 PMID: 14699058
  72. The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8.
    Genes Cells. 2004 Jul;9(7):611-8 PMID: 15265004
  73. The Amphimedon queenslandica genome and the evolution of animal complexity.
    Nature. 2010 Aug 5;466(7307):720-6 PMID: 20686567
  74. Solution structure of microtubule-associated protein light chain 3 and identification of its functional subdomains.
    J Biol Chem. 2005 Jul 1;280(26):24610-7 PMID: 15857831
  75. Dissecting the involvement of LC3B and GATE-16 in p62 recruitment into autophagosomes.
    Autophagy. 2011 Jul;7(7):683-8 PMID: 21460636
  76. Sequence logos: a new way to display consensus sequences.
    Nucleic Acids Res. 1990 Oct 25;18(20):6097-100 PMID: 2172928
  77. Mutation at the cargo-receptor binding site of Atg8 also affects its general autophagy regulation function.
    Autophagy. 2009 May;5(4):461-71 PMID: 19398890
  78. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4.
    EMBO J. 2007 Apr 4;26(7):1749-60 PMID: 17347651
  79. Post-translational modifications of three members of the human MAP1LC3 family and detection of a novel type of modification for MAP1LC3B.
    J Biol Chem. 2003 Aug 1;278(31):29278-87 PMID: 12740394
  80. Autophagy-related protein 8 (Atg8) family interacting motif in Atg3 mediates the Atg3-Atg8 interaction and is crucial for the cytoplasm-to-vacuole targeting pathway.
    J Biol Chem. 2010 Sep 17;285(38):29599-607 PMID: 20615880
  81. GEC1 interacts with the kappa opioid receptor and enhances expression of the receptor.
    J Biol Chem. 2006 Mar 24;281(12):7983-93 PMID: 16431922
  82. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy.
    Autophagy. 2009 Jul;5(5):690-8 PMID: 19363302
  83. Structural basis for sorting mechanism of p62 in selective autophagy.
    J Biol Chem. 2008 Aug 15;283(33):22847-57 PMID: 18524774
  84. Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis.
    J Cell Sci. 2009 Jul 15;122(Pt 14):2554-66 PMID: 19549685
  85. Meig1 deficiency causes a severe defect in mouse spermatogenesis.
    Dev Biol. 2010 Feb 15;338(2):158-67 PMID: 20004656
  86. p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy.
    Autophagy. 2010 Apr;6(3):330-44 PMID: 20168092
  87. Association of human transferrin receptor with GABARAP.
    FEBS Lett. 2002 May 8;518(1-3):101-6 PMID: 11997026
  88. Aut7p, a soluble autophagic factor, participates in multiple membrane trafficking processes.
    J Biol Chem. 2000 Oct 20;275(42):32966-73 PMID: 10837468
  89. Aut2p and Aut7p, two novel microtubule-associated proteins are essential for delivery of autophagic vesicles to the vacuole.
    EMBO J. 1998 Jul 1;17(13):3597-607 PMID: 9649430
  90. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation.
    EMBO J. 2001 Nov 1;20(21):5971-81 PMID: 11689437
  91. Structure of autophagy-related protein Atg8 from the silkworm Bombyx mori.
    Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Jul 1;66(Pt 7):787-90 PMID: 20606273
  92. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy.
    Mol Biol Cell. 2008 May;19(5):2092-100 PMID: 18321988
  93. Measurement of autophagy in cells and tissues.
    Methods Mol Biol. 2010;648:193-214 PMID: 20700714
  94. Involvement of LMA1 and GATE-16 family members in intracellular membrane dynamics.
    Biochim Biophys Acta. 2003 Aug 18;1641(2-3):145-56 PMID: 12914955
  95. The NMR structure of the autophagy-related protein Atg8.
    J Biomol NMR. 2010 Jul;47(3):237-41 PMID: 20428927
  96. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria.
    Nat Immunol. 2009 Nov;10(11):1215-21 PMID: 19820708
  97. GEC1-kappa opioid receptor binding involves hydrophobic interactions: GEC1 has chaperone-like effect.
    J Biol Chem. 2009 Jan 16;284(3):1673-85 PMID: 19001416
  98. Biogenesis and cargo selectivity of autophagosomes.
    Annu Rev Biochem. 2011;80:125-56 PMID: 21548784
  99. ATG systems from the protein structural point of view.
    Chem Rev. 2009 Apr;109(4):1587-98 PMID: 19236009
  100. Crystal structure of the GABA(A)-receptor-associated protein, GABARAP.
    EMBO Rep. 2002 Feb;3(2):183-9 PMID: 11818336
  101. 18 kDa microtubule-associated protein: identification as a new light chain (LC-3) of microtubule-associated protein 1 (MAP-1).
    FEBS Lett. 1987 Feb 9;212(1):145-8 PMID: 3803603
  102. Binding of the GABA(A) receptor-associated protein (GABARAP) to microtubules and microfilaments suggests involvement of the cytoskeleton in GABARAPGABA(A) receptor interaction.
    J Neurochem. 2000 Aug;75(2):644-55 PMID: 10899939
  103. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
    EMBO J. 2000 Nov 1;19(21):5720-8 PMID: 11060023
  104. Trypanosoma brucei ATG8: structural insights into autophagic-like mechanisms in protozoa.
    Autophagy. 2009 Nov;5(8):1085-91 PMID: 19736525
  105. Apg7p/Cvt2p: A novel protein-activating enzyme essential for autophagy.
    Mol Biol Cell. 1999 May;10(5):1367-79 PMID: 10233150
  106. LC3 conjugation system in mammalian autophagy.
    Int J Biochem Cell Biol. 2004 Dec;36(12):2503-18 PMID: 15325588
  107. The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway.
    J Cell Biol. 2000 Oct 16;151(2):263-76 PMID: 11038174
  108. Lung autophagic response following exposure of mice to whole body irradiation, with and without amifostine.
    Biochem Biophys Res Commun. 2011 Jan 7;404(1):552-8 PMID: 21145309
  109. Cdc48/p97 and Shp1/p47 regulate autophagosome biogenesis in concert with ubiquitin-like Atg8.
    J Cell Biol. 2010 Sep 20;190(6):965-73 PMID: 20855502
  110. The autophagy-associated Atg8 gene family operates both under favourable growth conditions and under starvation stresses in Arabidopsis plants.
    J Exp Bot. 2005 Nov;56(421):2839-49 PMID: 16157655
  111. The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans.
    Nature. 2008 Feb 14;451(7180):783-8 PMID: 18273011
  112. Cloning, expression patterns, and chromosome localization of three human and two mouse homologues of GABA(A) receptor-associated protein.
    Genomics. 2001 Jun 15;74(3):408-13 PMID: 11414770
  113. Selective transport of alpha-mannosidase by autophagic pathways: identification of a novel receptor, Atg34p.
    J Biol Chem. 2010 Sep 24;285(39):30019-25 PMID: 20639194
Article Info
Journal
Genome biology
Abbr.
Genome Biol
ISSN
1474-760X
DOI
10.1186/gb-2011-12-7-226
Published
2011-07-27
Epub
2011-00-27
Pages
226
Language
English
Region
England
NLM ID
100960660
PMCID
PMC3218822
Subset
IM
External Links
PubMed source DOI: 10.1186/gb-2011-12-7-226 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2