MAP1LC3B

Microtubule-associated protein 1 light chain 3 beta
PDB rendering based on 1ugm.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1V49​, 2LUE​, 2ZJD​, 3VTU​, 3VTV​, 3VTW​, 3WAO​, 3X0W​
Identifiers
Symbols	MAP1LC3B ; ATG8F; LC3B; MAP1A/1BLC3; MAP1LC3B-a
External IDs	OMIM: 609604 MGI: 1914693 HomoloGene: 69359 GeneCards: MAP1LC3B Gene
Gene ontology Molecular function • protein binding • microtubule binding • ubiquitin protein ligase binding Cellular component • pre-autophagosomal structure • autophagosome membrane • intracellular • mitochondrion • autophagosome • cytosol • microtubule • axoneme • endomembrane system • extrinsic component of membrane • organelle membrane • cytoplasmic vesicle Biological process • autophagosome assembly • mitophagy • cellular response to nitrogen starvation • nucleophagy • membrane fusion • regulation of mitophagy Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	81631	67443
Ensembl	ENSG00000140941	ENSMUSG00000031812
UniProt	Q9GZQ8	Q9CQV6
RefSeq (mRNA)	NM_022818	NM_026160
RefSeq (protein)	NP_073729	NP_080436
Location (UCSC)	Chr 16: 87.38 – 87.4 Mb	Chr 8: 121.59 – 121.6 Mb
PubMed search

Microtubule-associated proteins 1A/1B light chain 3B (hereafter referred to as LC3) is a protein that in humans is encoded by the MAP1LC3B gene.^[1] LC3 is a central protein in the autophagy pathway where it functions in autophagy substrate selection and autophagosome biogenesis. LC3 is the most widely used maker of autophagosomes.^[2]

Discovery

LC3 was originally identified as a microtubule associated protein in rat brain.^[3] However it was later found that the primary function of LC3 is in autophagy, a process that involves the bulk degradation of cytoplasmic components.

The ATG8 protein family

MAP1LC3B is a member of the highly conserved ATG8 protein family. ATG8 proteins are present in all known eukaryotic organisms. The animal ATG8 family comprises three subfamilies: (i) microtubule-associated protein 1 light chain 3 (MAP1LC3); (ii) Golgi-associated ATPase enhancer of 16 kDa (GATE-16); and (iii) γ-amino-butyric acid receptor-associate protein (GABARAP). MAP1LC3B is one of the four genes in the MAP1LC3 subfamily (others include MAP1LC3A, MAP1LC3C, and MAP1LC3B2).^[4]

Function

Cytoplasmic LC3

Newly synthesized LC3's C-terminus is hydroylzed by a cysteine protease called ATG4B exposing Gly120, termed LC3-I.^[5] LC3-I, through a series of ubiquitin-like reactions involving enzymes ATG7, ATG3, and ATG12-ATG5-ATG16, becomes conjugated to the head group of the lipid phosphatidylethanolamine.^[6] The lipid modified form of LC3, referred to as LC3-II, is believed to be involved in autophagosome membrane expansion and fusion events.^[7] However, the exact role of LC3 in the autophagic pathway is still discussed. And the question of whether LC3 is required for autophagy is debated since knockdown of MAP1LC3B is compensated by the other members of the MAP1LC3 subfamily. Previous studies showed that MAP1LC3B knock out mice develop normally, possibly due to a then unknown compensatory mechanism.^[8] Further work, however, demonstrated that LC3 is required for autophagy by simultaneously down-regulating all of the MAP1LC3 subfamily members.^[9] While yet another study argues that MAP1LC3 knockdown does to not affect bulk autophagy, whereas its GABARAP family members are crucial for the process.^[10][10] LC3 also functions—together with autophagy receptors (e.g. SQSTM1)--in the selective capture of cargo for autophagic degradation.^[11] Interestingly, independent of autophagosomes, a single soluble LC3 is associated with an approximately 500 kDa complex in the cytoplasm.^[12]

Nuclear LC3

The importance of the nuclear functions of autophagy proteins should not be underestimated. A large pool of LC3 is present in the nucleus of a variety of different cell types.^[13] In response to starvation, nuclear LC3 is deacetylated and trafficked out of the nucleus into the cytoplasm where it functions in autophagy.^[14] Nuclear LC3 interacts with lamin B1, and participates in the degradation of nuclear lamina.^[15] LC3 is also enriched in nucleoli via its triple arginine motif, and associates with a number of different nuclear and nucleolar constituents including: MAP1B, tubulin, and several ribosomal proteins.^[16]

Structure

LC3 shares structural homology with ubiquitin, and thus has been termed a ubiquitin-like protein.^[17] LC3 has a LDS (LIR docking site)/hydrophobic binding interface in the N terminus which interacts with LIR (LC3 Interacting Region) containing proteins.^[18] This domain is rich in hydrophobic amino acids, the mutation of which impairs the ability of LC3 binding with LIR containing proteins, many of which are autophagy cargo adapter proteins. For example, sequestosome (SQSTM1) interacts with Phe 52 and Leu53 aminoacids present in hydrophobic binding interface of LC3 and any mutation of these amino acids prevents LC3 interaction with SQSTM1.

References

1. "Entrez Gene: MAP1LC3B microtubule-associated protein 1 light chain 3 beta".
2. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, et al. (Jan 2016). "Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)". Autophagy 12 (1): 1–222. doi:10.1080/15548627.2015.1100356. PMID 26799652.
3. Mann SS, Hammarback JA (Apr 1994). "Molecular characterization of light chain 3. A microtubule binding subunit of MAP1A and MAP1B". The Journal of Biological Chemistry 269 (15): 11492–7. PMID 7908909.
4. Shpilka T, Weidberg H, Pietrokovski S, Elazar Z (2011-07-27). "Atg8: an autophagy-related ubiquitin-like protein family". Genome Biology 12 (7): 226. doi:10.1186/gb-2011-12-7-226. PMC 3218822. PMID 21867568.
5. Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y (Oct 2000). "The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway". The Journal of Cell Biology 151 (2): 263–76. doi:10.1083/jcb.151.2.263. PMID 11038174.
6. Ohsumi Y (Mar 2001). "Molecular dissection of autophagy: two ubiquitin-like systems". Nature Reviews. Molecular Cell Biology 2 (3): 211–6. doi:10.1038/35056522. PMID 11265251.
7. Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F, Elazar Z (Apr 2011). "LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis". Developmental Cell 20 (4): 444–54. doi:10.1016/j.devcel.2011.02.006. PMID 21497758.
8. Cann, Gordon M.; Guignabert, Christophe; Ying, Lihua; Deshpande, Niru; Bekker, Janine M.; Wang, Lingli; Zhou, Bin; Rabinovitch, Marlene (2008-01-01). "Developmental expression of LC3α and β: Absence of fibronectin or autophagy phenotype in LC3β knockout mice". Developmental Dynamics 237 (1): 187–195. doi:10.1002/dvdy.21392. ISSN 1097-0177.
9. Weidberg, Hilla; Shvets, Elena; Shpilka, Tomer; Shimron, Frida; Shinder, Vera; Elazar, Zvulun (2010-06-02). "LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis". The EMBO Journal 29 (11): 1792–1802. doi:10.1038/emboj.2010.74. PMC 2885923. PMID 20418806.
10. Szalai, Paula; Hagen, Linda Korseberg; Sætre, Frank; Luhr, Morten; Sponheim, Marianne; Øverbye, Anders; Mills, Ian G.; Seglen, Per O.; Engedal, Nikolai (2015-04-10). "Autophagic bulk sequestration of cytosolic cargo is independent of LC3, but requires GABARAPs". Experimental Cell Research 333 (1): 21–38. doi:10.1016/j.yexcr.2015.02.003.
11. Johansen T, Lamark T (Mar 2011). "Selective autophagy mediated by autophagic adapter proteins". Autophagy 7 (3): 279–96. doi:10.4161/auto.7.3.14487. PMC 3060413. PMID 21189453.
12. Kraft LJ, Nguyen TA, Vogel SS, Kenworthy AK (May 2014). "Size, stoichiometry, and organization of soluble LC3-associated complexes". Autophagy 10 (5): 861–77. doi:10.4161/auto.28175. PMC 4768459. PMID 24646892.
13. Drake KR, Kang M, Kenworthy AK. "Nucleocytoplasmic distribution and dynamics of the autophagosome marker EGFP-LC3". PloS One 5 (3): e9806. doi:10.1371/journal.pone.0009806. PMC 2843706. PMID 20352102.
14. Huang R, Xu Y, Wan W, Shou X, Qian J, You Z, Liu B, Chang C, Zhou T, Lippincott-Schwartz J, Liu W (Feb 2015). "Deacetylation of nuclear LC3 drives autophagy initiation under starvation". Molecular Cell 57 (3): 456–66. doi:10.1016/j.molcel.2014.12.013. PMID 25601754.
15. Dou Z, Xu C, Donahue G, Shimi T, Pan JA, Zhu J, Ivanov A, Capell BC, Drake AM, Shah PP, Catanzaro JM, Ricketts MD, Lamark T, Adam SA, Marmorstein R, Zong WX, Johansen T, Goldman RD, Adams PD, Berger SL (Nov 2015). "Autophagy mediates degradation of nuclear lamina". Nature 527 (7576): 105–9. doi:10.1038/nature15548. PMID 26524528.
16. Kraft LJ, Manral P, Dowler J, Kenworthy AK (Jan 2016). "Nuclear LC3 associates with slowly diffusing complexes that survey the nucleolus". Traffic. doi:10.1111/tra.12372. PMID 26728248.
17. Kouno T, Mizuguchi M, Tanida I, Ueno T, Kanematsu T, Mori Y, Shinoda H, Hirata M, Kominami E, Kawano K (Jul 2005). "Solution structure of microtubule-associated protein light chain 3 and identification of its functional subdomains". The Journal of Biological Chemistry 280 (26): 24610–7. doi:10.1074/jbc.M413565200. PMID 15857831.
18. Kraft LJ, Nguyen TA, Vogel SS, Kenworthy AK (May 2014). "Size, stoichiometry, and organization of soluble LC3-associated complexes". Autophagy 10 (5): 861–77. doi:10.4161/auto.28175. PMID 24646892.

Further reading

• Kraft LJ, Kenworthy AK (Jan 2012). "Imaging protein complex formation in the autophagy pathway: analysis of the interaction of LC3 and Atg4B(C74A) in live cells using Förster resonance energy transfer and fluorescence recovery after photobleaching". Journal of Biomedical Optics 17 (1): 011008. doi:10.1117/1.JBO.17.1.011008. PMC 3380812. PMID 22352642.
• Behrends C, Sowa ME, Gygi SP, Harper JW (Jul 2010). "Network organization of the human autophagy system". Nature 466 (7302): 68–76. doi:10.1038/nature09204. PMC 2901998. PMID 20562859.
• Tanida I, Ueno T, Kominami E (Dec 2004). "LC3 conjugation system in mammalian autophagy". The International Journal of Biochemistry & Cell Biology 36 (12): 2503–18. doi:10.1016/j.biocel.2004.05.009. PMID 15325588.
• Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (Nov 2000). "LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing". The EMBO Journal 19 (21): 5720–8. doi:10.1093/emboj/19.21.5720. PMC 305793. PMID 11060023.
• Tanida I, Tanida-Miyake E, Komatsu M, Ueno T, Kominami E (Apr 2002). "Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p". The Journal of Biological Chemistry 277 (16): 13739–44. doi:10.1074/jbc.M200385200. PMID 11825910.
• Tanida I, Tanida-Miyake E, Nishitani T, Komatsu M, Yamazaki H, Ueno T, Kominami E (Mar 2002). "Murine Apg12p has a substrate preference for murine Apg7p over three Apg8p homologs". Biochemical and Biophysical Research Communications 292 (1): 256–62. doi:10.1006/bbrc.2002.6645. PMID 11890701.
• He H, Dang Y, Dai F, Guo Z, Wu J, She X, Pei Y, Chen Y, Ling W, Wu C, Zhao S, Liu JO, Yu L (Aug 2003). "Post-translational modifications of three members of the human MAP1LC3 family and detection of a novel type of modification for MAP1LC3B". The Journal of Biological Chemistry 278 (31): 29278–87. doi:10.1074/jbc.M303800200. PMID 12740394.
• Tanida I, Sou YS, Ezaki J, Minematsu-Ikeguchi N, Ueno T, Kominami E (Aug 2004). "HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human Atg8 homologues and delipidates microtubule-associated protein light chain 3- and GABAA receptor-associated protein-phospholipid conjugates". The Journal of Biological Chemistry 279 (35): 36268–76. doi:10.1074/jbc.M401461200. PMID 15187094.
• Tanida I, Ueno T, Kominami E (Nov 2004). "Human light chain 3/MAP1LC3B is cleaved at its carboxyl-terminal Met121 to expose Gly120 for lipidation and targeting to autophagosomal membranes". The Journal of Biological Chemistry 279 (46): 47704–10. doi:10.1074/jbc.M407016200. PMID 15355958.