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=== Cytoplasmic LC3 ===
=== Cytoplasmic LC3 ===


Newly synthesized LC3's C-terminus is hydroylzed by a cysteine protease called [[ATG4B]] exposing Gly120, termed LC3-I.<ref>{{cite journal | vauthors = Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y | title = The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway | language = en | journal = The Journal of Cell Biology | volume = 151 | issue = 2 | pages = 263–76 | date = October 2000 | pmid = 11038174 | pmc = 2192639 | doi = 10.1083/jcb.151.2.263 }}</ref> LC3-I, through a series of ubiquitin-like reactions involving enzymes [[ATG7]], [[ATG3]], and [[ATG12]]-[[ATG5]]-[[ATG16L1|ATG16]], becomes conjugated to the head group of the lipid [[phosphatidylethanolamine]].<ref>{{cite journal | vauthors = Ohsumi Y | title = Molecular dissection of autophagy: two ubiquitin-like systems | journal = Nature Reviews. Molecular Cell Biology | volume = 2 | issue = 3 | pages = 211–6 | date = March 2001 | pmid = 11265251 | doi = 10.1038/35056522 }}</ref> The lipid modified form of LC3, referred to as LC3-II, is believed to be involved in autophagosome membrane expansion and fusion events.<ref>{{cite journal | vauthors = Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F, Elazar Z | title = LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis | language = English | journal = Developmental Cell | volume = 20 | issue = 4 | pages = 444–54 | date = April 2011 | pmid = 21497758 | doi = 10.1016/j.devcel.2011.02.006 }}</ref> 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.<ref>{{cite journal | vauthors = Cann GM, Guignabert C, Ying L, Deshpande N, Bekker JM, Wang L, Zhou B, Rabinovitch M | title = Developmental expression of LC3alpha and beta: absence of fibronectin or autophagy phenotype in LC3beta knockout mice | language = en | journal = Developmental Dynamics | volume = 237 | issue = 1 | pages = 187–95 | date = January 2008 | pmid = 18069693 | doi = 10.1002/dvdy.21392 }}</ref> Further work, however, demonstrated that LC3 is required for autophagy by simultaneously down-regulating all of the MAP1LC3 subfamily members.<ref>{{cite journal | vauthors = Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z | title = LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis | language = en | journal = The EMBO Journal | volume = 29 | issue = 11 | pages = 1792–802 | date = June 2010 | pmid = 20418806 | pmc = 2885923 | doi = 10.1038/emboj.2010.74 }}</ref> While yet another study argues that MAP1LC3 knockdown does to not affect bulk autophagy, whereas its [[GABARAP]] family members are crucial for the process.<ref name=":0">{{cite journal | vauthors = Szalai P, Hagen LK, Sætre F, Luhr M, Sponheim M, Øverbye A, Mills IG, Seglen PO, Engedal N | title = Autophagic bulk sequestration of cytosolic cargo is independent of LC3, but requires GABARAPs | journal = Experimental Cell Research | volume = 333 | issue = 1 | pages = 21–38 | date = April 2015 | pmid = 25684710 | doi = 10.1016/j.yexcr.2015.02.003 }}</ref><ref name=":0" /> LC3 also functions—together with autophagy receptors (e.g. [[Sequestosome 1|SQSTM1]])--in the selective capture of cargo for autophagic degradation.<ref>{{cite journal | vauthors = Johansen T, Lamark T | title = Selective autophagy mediated by autophagic adapter proteins | journal = Autophagy | volume = 7 | issue = 3 | pages = 279–96 | date = March 2011 | pmid = 21189453 | pmc = 3060413 | doi = 10.4161/auto.7.3.14487 }}</ref> Interestingly, independent of autophagosomes, a single soluble LC3 is associated with an approximately 500 kDa complex in the cytoplasm.<ref name="ReferenceA">{{cite journal | vauthors = Kraft LJ, Nguyen TA, Vogel SS, Kenworthy AK | title = Size, stoichiometry, and organization of soluble LC3-associated complexes | journal = Autophagy | volume = 10 | issue = 5 | pages = 861–77 | date = May 2014 | pmid = 24646892 | pmc = 4768459 | doi = 10.4161/auto.28175 }}</ref>
Newly synthesized LC3's C-terminus is hydroylzed by a cysteine protease called [[ATG4B]] exposing Gly120, termed LC3-I.<ref>{{cite journal | vauthors = Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y | title = The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway | language = en | journal = The Journal of Cell Biology | volume = 151 | issue = 2 | pages = 263–76 | date = October 2000 | pmid = 11038174 | pmc = 2192639 | doi = 10.1083/jcb.151.2.263 }}</ref> LC3-I, through a series of ubiquitin-like reactions involving enzymes [[ATG7]], [[ATG3]], and [[ATG12]]-[[ATG5]]-[[ATG16L1|ATG16]], becomes conjugated to the head group of the lipid [[phosphatidylethanolamine]].<ref>{{cite journal | vauthors = Ohsumi Y | title = Molecular dissection of autophagy: two ubiquitin-like systems | journal = Nature Reviews. Molecular Cell Biology | volume = 2 | issue = 3 | pages = 211–6 | date = March 2001 | pmid = 11265251 | doi = 10.1038/35056522 }}</ref> The lipid modified form of LC3, referred to as LC3-II, is believed to be involved in autophagosome membrane expansion and fusion events.<ref>{{cite journal | vauthors = Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F, Elazar Z | title = LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis | language = English | journal = Developmental Cell | volume = 20 | issue = 4 | pages = 444–54 | date = April 2011 | pmid = 21497758 | doi = 10.1016/j.devcel.2011.02.006 }}</ref> 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.<ref>{{cite journal | vauthors = Cann GM, Guignabert C, Ying L, Deshpande N, Bekker JM, Wang L, Zhou B, Rabinovitch M | title = Developmental expression of LC3alpha and beta: absence of fibronectin or autophagy phenotype in LC3beta knockout mice | language = en | journal = Developmental Dynamics | volume = 237 | issue = 1 | pages = 187–95 | date = January 2008 | pmid = 18069693 | doi = 10.1002/dvdy.21392 }}</ref> Further work, however, demonstrated that LC3 is required for autophagy by simultaneously down-regulating all of the MAP1LC3 subfamily members.<ref>{{cite journal | vauthors = Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z | title = LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis | language = en | journal = The EMBO Journal | volume = 29 | issue = 11 | pages = 1792–802 | date = June 2010 | pmid = 20418806 | pmc = 2885923 | doi = 10.1038/emboj.2010.74 }}</ref> While yet another study argues that MAP1LC3 knockdown does to not affect bulk autophagy, whereas its [[GABARAP]] family members are crucial for the process.<ref name=":0">{{cite journal | vauthors = Szalai P, Hagen LK, Sætre F, Luhr M, Sponheim M, Øverbye A, Mills IG, Seglen PO, Engedal N | title = Autophagic bulk sequestration of cytosolic cargo is independent of LC3, but requires GABARAPs | journal = Experimental Cell Research | volume = 333 | issue = 1 | pages = 21–38 | date = April 2015 | pmid = 25684710 | doi = 10.1016/j.yexcr.2015.02.003 }}</ref><ref name=":0" /> LC3 also functions—together with autophagy receptors (e.g. [[Sequestosome 1|SQSTM1]])--in the selective capture of cargo for autophagic degradation.<ref>{{cite journal | vauthors = Johansen T, Lamark T | title = Selective autophagy mediated by autophagic adapter proteins | journal = Autophagy | volume = 7 | issue = 3 | pages = 279–96 | date = March 2011 | pmid = 21189453 | pmc = 3060413 | doi = 10.4161/auto.7.3.14487 }}</ref> Independent of autophagosomes, a single soluble LC3 is associated with an approximately 500 kDa complex in the cytoplasm.<ref name="ReferenceA">{{cite journal | vauthors = Kraft LJ, Nguyen TA, Vogel SS, Kenworthy AK | title = Size, stoichiometry, and organization of soluble LC3-associated complexes | journal = Autophagy | volume = 10 | issue = 5 | pages = 861–77 | date = May 2014 | pmid = 24646892 | pmc = 4768459 | doi = 10.4161/auto.28175 }}</ref>


=== Nuclear LC3 ===
=== 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.<ref>{{cite journal | vauthors = Drake KR, Kang M, Kenworthy AK | title = Nucleocytoplasmic distribution and dynamics of the autophagosome marker EGFP-LC3 | journal = PLoS One | volume = 5 | issue = 3 | pages = e9806 | date = March 2010 | pmid = 20352102 | pmc = 2843706 | doi = 10.1371/journal.pone.0009806 }}</ref> In response to starvation, nuclear LC3 is deacetylated and trafficked out of the nucleus into the cytoplasm where it functions in autophagy.<ref>{{cite journal | vauthors = Huang R, Xu Y, Wan W, Shou X, Qian J, You Z, Liu B, Chang C, Zhou T, Lippincott-Schwartz J, Liu W | title = Deacetylation of nuclear LC3 drives autophagy initiation under starvation | language = English | journal = Molecular Cell | volume = 57 | issue = 3 | pages = 456–66 | date = February 2015 | pmid = 25601754 | doi = 10.1016/j.molcel.2014.12.013 }}</ref> Nuclear LC3 interacts with [[lamin B1]], and participates in the degradation of nuclear lamina.<ref>{{cite journal | vauthors = 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 | title = Autophagy mediates degradation of nuclear lamina | journal = Nature | volume = 527 | issue = 7576 | pages = 105–9 | date = November 2015 | pmid = 26524528 | pmc = 4824414 | doi = 10.1038/nature15548 }}</ref> LC3 is also enriched in [[Nucleolus|nucleoli]] via its triple arginine motif, and associates with a number of different nuclear and nucleolar constituents including: [[MAP1B]], [[tubulin]], and several ribosomal proteins.<ref>{{cite journal | vauthors = Kraft LJ, Manral P, Dowler J, Kenworthy AK | title = Nuclear LC3 Associates with Slowly Diffusing Complexes that Survey the Nucleolus | language = en | journal = Traffic | volume = 17 | issue = 4 | pages = 369–99 | date = April 2016 | pmid = 26728248 | doi = 10.1111/tra.12372 }}</ref>
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.<ref>{{cite journal | vauthors = Drake KR, Kang M, Kenworthy AK | title = Nucleocytoplasmic distribution and dynamics of the autophagosome marker EGFP-LC3 | journal = PLoS One | volume = 5 | issue = 3 | pages = e9806 | date = March 2010 | pmid = 20352102 | pmc = 2843706 | doi = 10.1371/journal.pone.0009806 }}</ref> In response to starvation, nuclear LC3 is deacetylated and trafficked out of the nucleus into the cytoplasm where it functions in autophagy.<ref>{{cite journal | vauthors = Huang R, Xu Y, Wan W, Shou X, Qian J, You Z, Liu B, Chang C, Zhou T, Lippincott-Schwartz J, Liu W | title = Deacetylation of nuclear LC3 drives autophagy initiation under starvation | language = English | journal = Molecular Cell | volume = 57 | issue = 3 | pages = 456–66 | date = February 2015 | pmid = 25601754 | doi = 10.1016/j.molcel.2014.12.013 }}</ref> Nuclear LC3 interacts with [[lamin B1]], and participates in the degradation of nuclear lamina.<ref>{{cite journal | vauthors = 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 | title = Autophagy mediates degradation of nuclear lamina | journal = Nature | volume = 527 | issue = 7576 | pages = 105–9 | date = November 2015 | pmid = 26524528 | pmc = 4824414 | doi = 10.1038/nature15548 }}</ref> LC3 is also enriched in [[Nucleolus|nucleoli]] via its triple arginine motif, and associates with a number of different nuclear and nucleolar constituents including: [[MAP1B]], [[tubulin]], and several ribosomal proteins.<ref>{{cite journal | vauthors = Kraft LJ, Manral P, Dowler J, Kenworthy AK | title = Nuclear LC3 Associates with Slowly Diffusing Complexes that Survey the Nucleolus | language = en | journal = Traffic | volume = 17 | issue = 4 | pages = 369–99 | date = April 2016 | pmid = 26728248 | doi = 10.1111/tra.12372 | pmc = 4975375 }}</ref>


== Structure ==
== Structure ==

Revision as of 03:38, 23 October 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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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 marker 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] 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.[12] 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

References

  1. ↑ "Entrez Gene: MAP1LC3B microtubule-associated protein 1 light chain 3 beta".
  2. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  3. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  4. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  5. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  6. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  7. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  8. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  9. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  10. ↑ 10.0 10.1 Lua error: Internal error: The interpreter has terminated with signal "24".
  11. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  12. ↑ 12.0 12.1 Lua error: Internal error: The interpreter has terminated with signal "24".
  13. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  14. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  15. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  16. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".
  17. ↑ Lua error: Internal error: The interpreter has terminated with signal "24".

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Further reading

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