ATG5

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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 (microtubule-associated proteins 1A/1B light chain 3B) conjugation to PE (phosphatidylethanolamine) to form LC3-II (LC3-phosphatidylethanolamine conjugate). 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.

ATG5 is known to be regulated via various stress induced transcription factors and protein kinases.

Structure

ATG5 comprises three domains: a ubiquitin-like N-terminal domain (UblA), a helix-rich domain (HR) and a ubiquitin-like C-terminal domain (UblB). The three domains are connected by two linker regions (L1 and L2). ATG5 also has an alpha-helix at the N terminus where on Lysine 130 conjugation with ATG12 occurs.[1] Both UblA and UbLB are composed of a five-stranded beta-sheet and two alpha-helices, a feature conserved in most ubiquitin and ubiquitin-like proteins. HR is composed of three long and one short alpha helices, forming a helix-bundle structure.[2]

Regulation

ATG5 is regulated by the p73 from the p53 family of transcription factors. DNA damage induces the p300 acetylase to acetylate p73 with the assistance of c-ABL tyrosine kinase. p73 translocates to the nucleus and acts as a transcription factor for ATG5 as well as other apoptotic and autophagic genes.[3]

Programmed Cell Death Protein 4 (PDCD4) is known to inhibit ATG5 expression via inhibition of protein translation. Two MA3 domains on PDCD4 bind to RNA-helicase EIF4A, preventing translation of ATG5 mRNA.[4]

Many protein kinases can regulate activity of the ATG5 protein. Phosphorylation by various kinases are required in order to achieve its active conformation. Under cell stress conditions, the growth arrest and DNA damage 45 beta (Gadd45ß) protein will interact with MAPK/ERK kinase kinase 4 (MEKK4) to form the Gadd45ß-MEKK4 signaling complex. This complex then activates and selectively targets p38 MAPK to the autophagosome to phosphorylate ATG5 at threonine 75. This leads to the inactivation of ATG5 and inhibition of autophagy.[5]

ATG5 can also be regulated post translationally by microRNA.[6]

Function

Autophagy

The ATG12-ATG5:ATG16L complex is responsible for elongation of the phagophore in the autophagy pathway. ATG12 is first activated by ATG7, proceeded by the conjugation of ATG5 to the complex by ATG10 via a ubiquitination-like enzymatic process. The ATG12-ATG5 then forms a homo-oligomeric complex with ATG16L.[7] With the help of ATG7 and ATG3, the ATG12-ATG5:ATG16L complex conjugates the C terminus of LC3-I to phosphatidylethanolamine in the phospholipid bilayer, allowing LC3 to associate with the membranes of the phagophore, becoming LC3-II. After formation of the autophagosome, the ATG12-ATG5:ATG16L complex dissociates from the autophagosome.[8][9][1]

Apoptosis

In instances of spontaneous apoptosis or induction of apoptosis via staurosporine, HL-60, or EOL cells, ATG5 undergoes N-terminal cleavage by Calpain-1 and Calpain-2. The cleaved ATG5 translocates from the cytosol to the mitochondria, where it interacts with Bcl-xL, triggering the release of Cytochrome c and activating caspases leading to the apoptotic pathway.[10][11] This function is independent of its role in autophagy, as it does not require interaction with ATG12.

Cell Cycle Arrest

In response to DNA damage, ATG5 expression is upregulated, increasing autophagy, preventing caspase activation and apoptosis. ATG5 is also responsible for G2/M arrest and mitotic catastrophe by leading to the phosphorylation of CDK1 and CHEK2, two important regulators of cell cycle arrest.[12] Furthermore, ATG5 is capable of translocating to the nucleus and interacting with survivin to disturb chromosome segregation by antagonistically competing with the ligand Aurora B.[12][13][13]

Clinical Significance

As a key regulator of autophagy, any suppression of the ATG5 protein or loss-of-function mutations in the ATG5 gene will negatively affect autophagy. As a result, deficiencies in the ATG5 protein and variations in the gene have been associated with various inflammatory and degenerative diseases as aggregrates of ubiquitinated targets are not cleared out via autophagy. Polymorphisms within the Atg5 gene have been associated with Behçet's disease,[14] systemic lupus erythematosus,[15] and lupus nephritis.[16] Mutations in the gene promoter for the Atg5 gene have been associated with sporadic Parkinson's disease[17] and childhood asthma.[18] Downregulation of ATG5 protein and mutations in the Atg5 gene have also been linked with prostate,[19] gastrointestinal[20] and colorectal[21] cancers as ATG5 plays a role in both cell apoptosis and cell cycle arrest. Upregulation of Atg5 on the other hand has been shown to suppress melanoma tumorigenesis through induction of cell senescence.[22] ATG5 also plays a protective role in M. tuberculosis infections by preventing PMN-mediated immunopathology.[23]

An Atg5−/− mutation in mice is known to be embryonic lethal.[24] When the mutation is induced only in mice neurons or hepatocytes, there is an accumulation of ubiquitin-positive inclusion bodies and a decrease in cell function.[25] Overexpression of ATG5 on the other hand has been linked to extend mouse lifespan.[26] In the brain, ATG5 is responsible for astrocyte differentiation through activation of the JAK2-STAT3 pathway via degradation of SOCS2.[27] Furthermore, reduction of ATG5 levels in mice brains leads to a suppression in differentiation and increase in cell proliferation of cortical neural progenitor cells through regulation of β-Catenin.[28]

References

  1. ↑ 1.0 1.1 Otomo C, Metlagel Z, Takaesu G, Otomo T (January 2013). "Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy". Nature Structural & Molecular Biology. 20 (1): 59–66. doi:10.1038/nsmb.2431. PMC 3540207. PMID 23202584.
  2. ↑ Matsushita M, Suzuki NN, Obara K, Fujioka Y, Ohsumi Y, Inagaki F (March 2007). "Structure of Atg5.Atg16, a complex essential for autophagy" (PDF). The Journal of Biological Chemistry. 282 (9): 6763–72. doi:10.1074/jbc.m609876200. PMID 17192262.
  3. ↑ Costanzo A, Merlo P, Pediconi N, Fulco M, Sartorelli V, Cole PA, Fontemaggi G, Fanciulli M, Schiltz L, Blandino G, Balsano C, Levrero M (January 2002). "DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes". Molecular Cell. 9 (1): 175–86. doi:10.1016/s1097-2765(02)00431-8. PMID 11804596.
  4. ↑ Song X, Zhang X, Wang X, Zhu F, Guo C, Wang Q, Shi Y, Wang J, Chen Y, Zhang L (May 2013). "Tumor suppressor gene PDCD4 negatively regulates autophagy by inhibiting the expression of autophagy-related gene ATG5". Autophagy. 9 (5): 743–55. doi:10.4161/auto.24069. PMC 3669183. PMID 23486359.
  5. ↑ Keil E, Höcker R, Schuster M, Essmann F, Ueffing N, Hoffman B, Liebermann DA, Pfeffer K, Schulze-Osthoff K, Schmitz I (February 2013). "Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy". Cell Death and Differentiation. 20 (2): 321–32. doi:10.1038/cdd.2012.129. PMC 3554344. PMID 23059785.
  6. ↑ Tekirdag KA, Korkmaz G, Ozturk DG, Agami R, Gozuacik D (March 2013). "MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5". Autophagy. 9 (3): 374–85. doi:10.4161/auto.23117. PMC 3590257. PMID 23322078.
  7. ↑ Wesselborg S, Stork B (December 2015). "Autophagy signal transduction by ATG proteins: from hierarchies to networks". Cellular and Molecular Life Sciences. 72 (24): 4721–57. doi:10.1007/s00018-015-2034-8. PMC 4648967. PMID 26390974.
  8. ↑ Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN, Cho DH, Choi B, Lee H, Kim JH, Mizushima N, Oshumi Y, Jung YK (May 2005). "Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death". The Journal of Biological Chemistry. 280 (21): 20722–9. doi:10.1074/jbc.M413934200. PMID 15778222.
  9. ↑ Mehrpour M, Esclatine A, Beau I, Codogno P (July 2010). "Overview of macroautophagy regulation in mammalian cells". Cell Research. 20 (7): 748–62. doi:10.1038/cr.2010.82. PMID 20548331.
  10. ↑ Codogno P, Meijer AJ (October 2006). "Atg5: more than an autophagy factor". Nature Cell Biology. 8 (10): 1045–7. doi:10.1038/ncb1006-1045. PMID 17013414.
  11. ↑ Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon HU (October 2006). "Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis". Nature Cell Biology. 8 (10): 1124–32. doi:10.1038/ncb1482. PMID 16998475.
  12. ↑ 12.0 12.1 Simon HU, Friis R (January 2014). "ATG5: a distinct role in the nucleus". Autophagy. 10 (1): 176–7. doi:10.4161/auto.26916. PMC 4389873. PMID 24248263.
  13. ↑ 13.0 13.1 Maskey D, Yousefi S, Schmid I, Zlobec I, Perren A, Friis R, Simon HU (2013-08-15). "ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy". Nature Communications. 4: 2130. doi:10.1038/ncomms3130. PMC 3753548. PMID 23945651.
  14. ↑ Zheng M, Yu H, Zhang L, Li H, Liu Y, Kijlstra A, Yang P (December 2015). "Association of ATG5 Gene Polymorphisms With Behçet's Disease and ATG10 Gene Polymorphisms With VKH Syndrome in a Chinese Han Population". Investigative Ophthalmology & Visual Science. 56 (13): 8280–7. doi:10.1167/iovs.15-18035. PMID 26747760.
  15. ↑ Zhang YM, Cheng FJ, Zhou XJ, Qi YY, Zhao MH, Zhang H (June 2015). "Rare Variants of ATG5 Are Likely to Be Associated With Chinese Patients With Systemic Lupus Erythematosus". Medicine. 94 (22): e939. doi:10.1097/MD.0000000000000939. PMC 4616363. PMID 26039132.
  16. ↑ Zhang YM, Cheng FJ, Zhou XJ, Qi YY, Hou P, Zhao MH, Zhang H (2015). "Detecting Genetic Associations between ATG5 and Lupus Nephritis by trans-eQTL". Journal of Immunology Research. 2015: 153132. doi:10.1155/2015/153132. PMC 4609853. PMID 26509176.
  17. ↑ Chen D, Zhu C, Wang X, Feng X, Pang S, Huang W, Hawley RG, Yan B (March 2013). "A novel and functional variant within the ATG5 gene promoter in sporadic Parkinson's disease". Neuroscience Letters. 538: 49–53. doi:10.1016/j.neulet.2013.01.044. PMID 23384565.
  18. ↑ Martin LJ, Gupta J, Jyothula SS, Butsch Kovacic M, Biagini Myers JM, Patterson TL, Ericksen MB, He H, Gibson AM, Baye TM, Amirisetty S, Tsoras AM, Sha Y, Eissa NT, Hershey GK (2012). "Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma". PLOS One. 7 (4): e33454. doi:10.1371/journal.pone.0033454. PMC 3335039. PMID 22536318.
  19. ↑ Li X, Li C, Zhu LH (January 2015). "[Correlation of autophagy-associated gene Atg5 with tumorigenesis of prostate cancer]". Zhonghua Nan Ke Xue = National Journal of Andrology. 21 (1): 31–4. PMID 25707136.
  20. ↑ An CH, Kim MS, Yoo NJ, Park SW, Lee SH (July 2011). "Mutational and expressional analyses of ATG5, an autophagy-related gene, in gastrointestinal cancers". Pathology, Research and Practice. 207 (7): 433–7. doi:10.1016/j.prp.2011.05.002. PMID 21664058.
  21. ↑ Cho DH, Jo YK, Kim SC, Park IJ, Kim JC (September 2012). "Down-regulated expression of ATG5 in colorectal cancer". Anticancer Research. 32 (9): 4091–6. PMID 22993366.
  22. ↑ Liu H, He Z, Simon HU (February 2014). "Autophagy suppresses melanoma tumorigenesis by inducing senescence". Autophagy. 10 (2): 372–3. doi:10.4161/auto.27163. PMC 5396100. PMID 24300435.
  23. ↑ Kimmey JM, Huynh JP, Weiss LA, Park S, Kambal A, Debnath J, Virgin HW, Stallings CL (December 2015). "Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection". Nature. 528 (7583): 565–9. doi:10.1038/nature16451. PMC 4842313. PMID 26649827.
  24. ↑ Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (December 2004). "The role of autophagy during the early neonatal starvation period". Nature. 432 (7020): 1032–6. doi:10.1038/nature03029. PMID 15525940.
  25. ↑ Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (June 2006). "Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice". Nature. 441 (7095): 885–9. doi:10.1038/nature04724. PMID 16625204.
  26. ↑ Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, Jung S, Jung YK (2013). "Overexpression of Atg5 in mice activates autophagy and extends lifespan". Nature Communications. 4: 2300. doi:10.1038/ncomms3300. PMC 3753544. PMID 23939249.
  27. ↑ Wang S, Li B, Qiao H, Lv X, Liang Q, Shi Z, Xia W, Ji F, Jiao J (October 2014). "Autophagy-related gene Atg5 is essential for astrocyte differentiation in the developing mouse cortex". EMBO Reports. 15 (10): 1053–61. doi:10.15252/embr.201338343. PMC 4253845. PMID 25227738.
  28. ↑ Lv X, Jiang H, Li B, Liang Q, Wang S, Zhao Q, Jiao J (August 2014). "The crucial role of Atg5 in cortical neurogenesis during early brain development". Scientific Reports. 4: 6010. doi:10.1038/srep06010. PMC 4127499. PMID 25109817.

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