MAP1LC3B

Last updated
MAP1LC3B
Protein MAP1LC3B PDB 1ugm.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MAP1LC3B , ATG8F, LC3B, MAP1A/1BLC3, MAP1LC3B-a, microtubule associated protein 1 light chain 3 beta
External IDs OMIM: 609604 MGI: 1914693 HomoloGene: 69359 GeneCards: MAP1LC3B
Orthologs
SpeciesHumanMouse
Entrez

81631

67443

Ensembl

ENSG00000140941

ENSMUSG00000031812

UniProt

Q9GZQ8

Q9CQV6

RefSeq (mRNA)

NM_022818

NM_026160
NM_001364358

RefSeq (protein)

NP_073729

NP_080436
NP_001351287

Location (UCSC) Chr 16: 87.38 – 87.4 Mb Chr 8: 122.32 – 122.33 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] 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 marker of autophagosomes. [6]

Discovery

LC3 was originally identified as a microtubule associated protein in rat brain. [7] 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 ). [8]

Function

Cytoplasmic LC3

Newly synthesized LC3's C-terminus is hydrolyzed by a cysteine protease called ATG4B exposing Gly120, termed LC3-I. [9] 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. [10] The lipid modified form of LC3, referred to as LC3-II, is believed to be involved in autophagosome membrane expansion and fusion events. [11] 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. [12] Further work, however, demonstrated that LC3 is required for autophagy by simultaneously down-regulating all of the MAP1LC3 subfamily members. [13] While yet another study argues that MAP1LC3 knockdown does not affect bulk autophagy, whereas its GABARAP family members are crucial for the process. [14] LC3 also functions—together with autophagy receptors (e.g. SQSTM1)--in the selective capture of cargo for autophagic degradation. [15] Independent of autophagosomes, a single soluble LC3 is associated with an approximately 500 kDa complex in the cytoplasm. [16]

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. [17] In response to starvation, nuclear LC3 is deacetylated and trafficked out of the nucleus into the cytoplasm where it functions in autophagy. [18] Nuclear LC3 interacts with lamin B1, and participates in the degradation of nuclear lamina. [19] 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. [20]

Structure

LC3 shares structural homology with ubiquitin, and therefore has been termed a ubiquitin-like protein. [21] LC3 has a LDS (LIR docking site)/hydrophobic binding interface in the N terminus which interacts with LIR (LC3 Interacting Region) containing proteins. [16] 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.

Post-translational regulation

Related Research Articles

<span class="mw-page-title-main">Autophagy</span> Cellular catabolic process in which cells digest parts of their own cytoplasm

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

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<span class="mw-page-title-main">Vojo Deretic</span> American geneticist

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<span class="mw-page-title-main">GABARAP</span> Protein-coding gene in the species Homo sapiens

Gamma-aminobutyric acid receptor-associated protein is a protein that in humans is encoded by the GABARAP gene.

<span class="mw-page-title-main">ATG5</span> Protein-coding gene in the species Homo sapiens

Autophagy related 5 (ATG5) is a protein that, in humans, is encoded by the ATG5 gene located on Chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic vesicles. It is activated by ATG7 and forms a complex with ATG12 and ATG16L1. This complex is necessary for LC3-I conjugation to PE (phosphatidylethanolamine) to form LC3-II. ATG5 can also act as a pro-apoptotic molecule targeted to the mitochondria. Under low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin.

<span class="mw-page-title-main">MAP1LC3A</span> Protein-coding gene in the species Homo sapiens

Microtubule-associated proteins 1A/1B light chain 3A is a protein that in humans is encoded by the MAP1LC3A gene. Two transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">ATG4B</span> Protein-coding gene in the species Homo sapiens

Cysteine protease ATG4B is an enzyme that in humans is encoded by the ATG4B gene.

<span class="mw-page-title-main">GABARAPL2</span> Protein-coding gene in the species Homo sapiens

Gamma-aminobutyric acid receptor-associated protein-like 2 is a protein that in humans is encoded by the GABARAPL2 gene.

<span class="mw-page-title-main">ATG12</span> Protein-coding gene in the species Homo sapiens

Autophagy related 12 is a protein that in humans is encoded by the ATG12 gene.

<span class="mw-page-title-main">ULK1</span> Enzyme found in humans

ULK1 is an enzyme that in humans is encoded by the ULK1 gene.

<span class="mw-page-title-main">ATG7</span> Protein-coding gene in the species Homo sapiens

Autophagy related 7 is a protein in humans encoded by ATG7 gene. Related to GSA7; APG7L; APG7-LIKE.

<span class="mw-page-title-main">ATG8</span>

Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for autophagy in eukaryotes. Even though there are homologues in animals, this article mainly focuses on its role in lower eukaryotes such as Saccharomyces cerevisiae.

AuTophaGy related 1 (Atg1) is a 101.7kDa serine/threonine kinase in S.cerevisiae, encoded by the gene ATG1. It is essential for the initial building of the autophagosome and Cvt vesicles. In a non-kinase role it is - through complex formation with Atg13 and Atg17 - directly controlled by the TOR kinase, a sensor for nutrient availability.

<span class="mw-page-title-main">IRGs</span>

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In molecular biology, autophagy related 3 (Atg3) is the E2 enzyme for the LC3 lipidation process. It is essential for autophagy. The super protein complex, the Atg16L complex, consists of multiple Atg12-Atg5 conjugates. Atg16L has an E3-like role in the LC3 lipidation reaction. The activated intermediate, LC3-Atg3 (E2), is recruited to the site where the lipidation takes place.

<span class="mw-page-title-main">Yoshinori Ohsumi</span> Japanese cell biologist

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<span class="mw-page-title-main">Ubiquitin-like protein</span> Family of small proteins

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<span class="mw-page-title-main">Rubicon (protein)</span> Human protein involved in autophagy regulation

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000140941 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031812 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: MAP1LC3B microtubule-associated protein 1 light chain 3 beta".
  6. ↑ Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, 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. PMC   4835977 . PMID   26799652.
  7. ↑ Mann SS, Hammarback JA (April 1994). "Molecular characterization of light chain 3. A microtubule binding subunit of MAP1A and MAP1B". The Journal of Biological Chemistry. 269 (15): 11492–7. doi: 10.1016/S0021-9258(19)78150-2 . PMID   7908909.
  8. ↑ Shpilka T, Weidberg H, Pietrokovski S, Elazar Z (July 2011). "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.
  9. ↑ Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y (October 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. PMC   2192639 . PMID   11038174.
  10. ↑ Ohsumi Y (March 2001). "Molecular dissection of autophagy: two ubiquitin-like systems". Nature Reviews. Molecular Cell Biology. 2 (3): 211–6. doi:10.1038/35056522. PMID   11265251. S2CID   38001477.
  11. ↑ Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F, Elazar Z (April 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.
  12. ↑ Cann GM, Guignabert C, Ying L, Deshpande N, Bekker JM, Wang L, Zhou B, Rabinovitch M (January 2008). "Developmental expression of LC3alpha and beta: absence of fibronectin or autophagy phenotype in LC3beta knockout mice". Developmental Dynamics. 237 (1): 187–95. doi:10.1002/dvdy.21392. PMID   18069693. S2CID   86562625.
  13. ↑ Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z (June 2010). "LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis". The EMBO Journal. 29 (11): 1792–802. doi:10.1038/emboj.2010.74. PMC   2885923 . PMID   20418806.
  14. ↑ Szalai P, Hagen LK, Sætre F, Luhr M, Sponheim M, Øverbye A, Mills IG, Seglen PO, Engedal N (April 2015). "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. PMID   25684710.
  15. ↑ Johansen T, Lamark T (March 2011). "Selective autophagy mediated by autophagic adapter proteins". Autophagy. 7 (3): 279–96. doi:10.4161/auto.7.3.14487. PMC   3060413 . PMID   21189453.
  16. 1 2 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.
  17. ↑ Drake KR, Kang M, Kenworthy AK (March 2010). "Nucleocytoplasmic distribution and dynamics of the autophagosome marker EGFP-LC3". PLOS ONE. 5 (3): e9806. Bibcode:2010PLoSO...5.9806D. doi: 10.1371/journal.pone.0009806 . PMC   2843706 . PMID   20352102.
  18. ↑ Huang R, Xu Y, Wan W, Shou X, Qian J, You Z, Liu B, Chang C, Zhou T, Lippincott-Schwartz J, Liu W (February 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.
  19. ↑ 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 (November 2015). "Autophagy mediates degradation of nuclear lamina". Nature. 527 (7576): 105–9. Bibcode:2015Natur.527..105D. doi:10.1038/nature15548. PMC   4824414 . PMID   26524528.
  20. ↑ Kraft LJ, Manral P, Dowler J, Kenworthy AK (April 2016). "Nuclear LC3 Associates with Slowly Diffusing Complexes that Survey the Nucleolus". Traffic. 17 (4): 369–99. doi:10.1111/tra.12372. PMC   4975375 . PMID   26728248.
  21. ↑ Kouno T, Mizuguchi M, Tanida I, Ueno T, Kanematsu T, Mori Y, Shinoda H, Hirata M, Kominami E, Kawano K (July 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.

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