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ULK1

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ULK1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesULK1, ATG1, ATG1A, UNC51, Unc51.1, hATG1, unc-51 like autophagy activating kinase 1
External IDsOMIM: 603168; MGI: 1270126; HomoloGene: 2640; GeneCards: ULK1; OMA:ULK1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8408

22241

Ensembl

ENSG00000177169

ENSMUSG00000029512

UniProt

O75385

O70405

RefSeq (mRNA)

NM_003565

NM_009469
NM_001347394

RefSeq (protein)

NP_003556

NP_001334323
NP_033495

Location (UCSC)Chr 12: 131.89 – 131.92 MbChr 5: 110.93 – 110.96 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ULK1 is an enzyme that in humans is encoded by the ULK1 gene.[5][6]

Unc-51 like autophagy activating kinase (ULK1/2) are two similar isoforms of an enzyme that in humans are encoded by the ULK1/2 genes.[5][6] It is specifically a kinase that is involved with autophagy, particularly in response to amino acid withdrawal. Not many studies have been done comparing the two isoforms, but some differences have been recorded.[7]

Function

Ulk1/2 is an important protein in autophagy for mammalian cells, and is homologous to ATG1 in yeast. It is part of the ULK1-complex, which is needed in early steps of autophagosome biogenesis. The ULK1 complex also consists of the FAK family kinase interacting protein of 200 kDa (FIP200 or RB1CC1) and the HORMA (Hop/Rev7/Mad2) domain-containing proteins ATG13 and ATG101.[8] ULK1, specifically, appears to be the most essential for autophagy and is activated under conditions of nutrient deprivation by several upstream signals which is followed by the initiation of autophagy.[9] However, ULK1 and ULK2 show high functional redundancy; studies have shown that ULK2 can compensate for the loss of ULK1. Nutrient dependent autophagy is only fully inhibited if both ULK1 and ULK2 are knocked out.

ULK1 has many downstream phosphorylation targets to aid in this induction of the isolation membrane/ autophagosome. Recently, a mechanism for autophagy has been elucidated. Models have proposed that the active ULK1 directly phosphorylates Beclin-1 at Ser 14 and activates the pro-autophagy class III phosphoinositide 3-kinase (PI(3)K), VPS34 complex, to promote autophagy induction and maturation.[10]

Ulk1/2 is negatively regulated by mTORC1 activity, which is active during anabolic-type environmental cues. In contrast, Ulk1/2 is activated by AMPK activity from starvation signals.[11]

Ulk1/2 may have critical roles beyond what ATG1 performs in yeast, including neural growth and development.

Interactions

When active, mTORC1 inhibits autophagy by phosphorylating both ULK1 and ATG13, which reduces the kinase activity of ULK1. Under starvation conditions, mTORC1 is inhibited and dissociates from ULK1 allowing it to become active. AMPK is activated when intracellular AMP increases under starvation conditions, which inactivate mTORC1, and thus indirectly activate ULK1. AMPK also directly phosphorylates ULK1 at multiple sites in the linker region between the kinase and C-terminal domains.[8]

ULK1 can phosphorylate itself as well as ATG13 and RB1CC1, which are regulatory proteins; however, the direct substrate of ULK1 has not been identified although recent studies suggest it phosphorylates Beclin-1.[citation needed]

Upon proteotoxic stresses, ULK1 has been found to phosphorylate the adaptor protein p62/SQSTM1, which increases the binding affinity of p62/SQSTM1 for ubiquitin.[8][12]

ULK1 has been shown to interact with Raptor, Beclin1, Class-III-PI3K, GABARAPL2,[13] GABARAP,[13][14] SYNGAP1[15] and SDCBP.[15]

Structure

ULK1 is a 112-kDa protein. It contains a N-terminal kinase domain, a serine-proline rich region, and a C-terminal interacting domain. The serine-proline rich region has been shown experimentally to be the site of phosphorylation by mTORC1 and AMPK—a negative and positive regulator of ULK1 activity, respectively. The C-terminal domain contains two microtubule-interacting and transport (MIT) domains and acts as a scaffold which links ULK1, ATG13, and FIFP200 together to form a complex that is essential to initiate autophagy. Early autophagy targeting/tethering (EAT) domains in the C-terminus are arranged as MIT domains consisting of two three-helix bundles. MIT domains also mediate interactions with membranes. The N-terminus contains a serine-threonine kinase domain. ULK1 also contains a large activation loop between the N and C terminus that is positively charged. This region may regulate kinase activity and play a role in recognizing different substrates. ULK1 and ULK2 share significant homology in both the C-terminal and N-terminal domains.[9]

Post-translational modifications

ULK1 is phosphorylated by AMPK on Ser317 and Ser777 to activate autophagy; mTOR participates in inhibitory phosphorylation of ULK1 on Ser757.[16] Additionally, ULK1 can auto-phosphorylate itself at Thr180 to facilitate self activation.[17]

Viral targeting of ULK1 appears to disrupt host autophagy. Coxsackievirus B3 viral proteinase 3C can proteolytically process ULK1 by cleaving after glutamine (Q) residue 524, separating the N-terminal kinase domain from C-terminal early autophagy targeting/tethering (EAT) domain.[18]

Given ULK1's role in autophagy, many diseases such as cancer,[19] neurodegenerative disorders, neurodevelopment disorders,[20] and Crohn's disease[21] could be attributed to any impairments in autophagy regulation.

In cancer specifically, ULK1 has become an attractive therapeutic target.[citation needed] Since autophagy acts as a cell survival trait for cells, it enables tumors (once they are already formed) to survive energy deprivation and other stresses such as chemotherapeutics. For that reason, inhibiting autophagy may prove to be beneficial. Thus, inhibitors have been targeted towards ULK1.[22]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000177169 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029512 – 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. ^ Kuroyanagi H, Yan J, Seki N, Yamanouchi Y, Suzuki Y, Takano T, et al. (July 1998). "Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment". Genomics. 51 (1): 76–85. doi:10.1006/geno.1998.5340. PMID 9693035.
  6. ^ "Entrez Gene: ULK1 unc-51-like kinase 1 (C. elegans)".
  7. ^ Ro SH, Jung CH, Hahn WS, Xu X, Kim YM, Yun YS, et al. (December 2013). "Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes". Autophagy. 9 (12): 2103–2114. doi:10.4161/auto.26563. PMC 4028344. PMID 24135897.
  8. ^ a b c Lin MG, Hurley JH (April 2016). "Structure and function of the ULK1 complex in autophagy". Current Opinion in Cell Biology. 39: 61–68. doi:10.1016/j.ceb.2016.02.010. PMC 4828305. PMID 26921696.
  9. ^ a b Lazarus MB, Novotny CJ, Shokat KM (January 2015). "Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors". ACS Chemical Biology. 10 (1): 257–261. doi:10.1021/cb500835z. PMC 4301081. PMID 25551253.
  10. ^ Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, et al. (July 2013). "ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase". Nature Cell Biology. 15 (7): 741–750. doi:10.1038/ncb2757. PMC 3885611. PMID 23685627.
  11. ^ Kim J, Kundu M, Viollet B, Guan KL (February 2011). "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1". Nature Cell Biology. 13 (2): 132–141. doi:10.1038/ncb2152. PMC 3987946. PMID 21258367.
  12. ^ Lim J, Lachenmayer ML, Wu S, Liu W, Kundu M, Wang R, et al. (2015). "Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates". PLOS Genetics. 11 (2): e1004987. doi:10.1371/journal.pgen.1004987. PMC 4344198. PMID 25723488.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ a b Okazaki N, Yan J, Yuasa S, Ueno T, Kominami E, Masuho Y, et al. (December 2000). "Interaction of the Unc-51-like kinase and microtubule-associated protein light chain 3 related proteins in the brain: possible role of vesicular transport in axonal elongation". Brain Research. Molecular Brain Research. 85 (1–2): 1–12. doi:10.1016/s0169-328x(00)00218-7. PMID 11146101.
  14. ^ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. 89.
  15. ^ a b Tomoda T, Kim JH, Zhan C, Hatten ME (March 2004). "Role of Unc51.1 and its binding partners in CNS axon outgrowth". Genes & Development. 18 (5): 541–558. doi:10.1101/gad.1151204. PMC 374236. PMID 15014045.
  16. ^ Kim J, Kundu M, Viollet B, Guan KL (February 2011). "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1". Nature Cell Biology. 13 (2): 132–141. doi:10.1038/ncb2152. PMC 3987946. PMID 21258367.
  17. ^ Xie Y, Kang R, Sun X, Zhong M, Huang J, Klionsky DJ, Tang D (2015-01-02). "Posttranslational modification of autophagy-related proteins in macroautophagy". Autophagy. 11 (1): 28–45. doi:10.4161/15548627.2014.984267. PMC 4502723. PMID 25484070.
  18. ^ Mohamud Y, Shi J, Tang H, Xiang P, Xue YC, Liu H, et al. (November 2020). "Coxsackievirus infection induces a non-canonical autophagy independent of the ULK and PI3K complexes". Scientific Reports. 10 (1): 19068. doi:10.1038/s41598-020-76227-7. PMC 7642411. PMID 33149253.
  19. ^ Chen MB, Ji XZ, Liu YY, Zeng P, Xu XY, Ma R, et al. (May 2017). "Ulk1 over-expression in human gastric cancer is correlated with patients' T classification and cancer relapse". Oncotarget. 8 (20): 33704–33712. doi:10.18632/oncotarget.16734. PMC 5464904. PMID 28410240.
  20. ^ Lee KM, Hwang SK, Lee JA (September 2013). "Neuronal autophagy and neurodevelopmental disorders". Experimental Neurobiology. 22 (3): 133–142. doi:10.5607/en.2013.22.3.133. PMC 3807000. PMID 24167408.
  21. ^ Henckaerts L, Cleynen I, Brinar M, John JM, Van Steen K, Rutgeerts P, Vermeire S (June 2011). "Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease". Inflammatory Bowel Diseases. 17 (6): 1392–1397. doi:10.1002/ibd.21486. PMID 21560199. S2CID 44342825.
  22. ^ Egan DF, Chun MG, Vamos M, Zou H, Rong J, Miller CJ, et al. (July 2015). "Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates". Molecular Cell. 59 (2): 285–297. doi:10.1016/j.molcel.2015.05.031. PMC 4530630. PMID 26118643.

Further reading

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