EIF2AK3

EIF2AK3
Identifiers
AliasesEIF2AK3, PEK, PERK, WRS, eukaryotic translation initiation factor 2 alpha kinase 3
External IDsOMIM: 604032; MGI: 1341830; GeneCards: EIF2AK3
Available structures
PDBOrtholog search: PDBe RCSB
Enzyme activity
EC #BRENDAExPASyKEGGMetaCyc
2.7.10.2↗↗↗↗
2.7.11.1↗↗↗↗
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

9451

13666

Ensembl

ENSG00000172071

ENSMUSG00000031668

UniProt

Q9NZJ5

Q9Z2B5

RefSeq (mRNA)

NM_001313915
NM_004836

NM_010121
NM_001313918

RefSeq (protein)

NP_001300844
NP_004827

NP_001300847
NP_034251

Location (UCSC)Chr 2: 88.56 – 88.69 MbChr 6: 70.82 – 70.88 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is an enzyme that in humans is encoded by the EIF2AK3 gene.[5][6][7][8]

Function

The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins.[6] PERK also has other phosphorylation substrates and has functions in regulating mitochondrial homeostasis that are independent of its kinase activity.[9][10][11][12] Because of this functional complexity, the biochemical mechanisms underlying the diverse defects observed in PERK-deficient humans and mice remain unclear.

PERK (EIF2AK3) deficiency in humans and mice denoted as the Wolcott-Rallison Syndrome (WRS) display a complex array of abnormalities including permanent neonatal diabetes, exocrine pancreas necrosis, postnatal growth retardation, osteopenia, skeletal dysplasia, acute liver failure, and death during infancy.[13][14][15] Based on cell culture experiments using PERK-deficient fibroblast that preceded, the initial studies of PERK-deficient mice proposed that these anomalies were all due to a dysfunction in regulating the ER stress/Unfolded protein response and uncontrolled global protein synthesis, and specifically that permanent neonatal diabetes resulted from uncontrolled ER stress and apoptotic loss of pancreatic β cells.[14][15] Subsequent genetic studies utilizing tissue-specific PERK KO and tissue-targeted transgenic knockin mice did not support this explanation for the development of diabetes in PERK-deficient mice. Analysis of mice with β-cell-specific PERK deficiency found that reduced β-cell mass resulted primarily from impaired β-cell proliferation and differentiation during fetal and neonatal development rather than cell death and apoptosis.[16] Additional studies showed that PERK-deficient β cells exhibit defects in proinsulin trafficking and secretory-pathway quality control that are not explained by uncontrolled global protein synthesis.[17][18] PERK has also been shown to regulate intracellular calcium dynamics and insulin secretion in β cells under physiological conditions, which is independent of phosphorylation of eIF2α.[19][20][21] Studies in PERK-deficient mice have also demonstrated that major systemic consequences of PERK deficiency can be non-cell-autonomous. Restoration of PERK expression exclusively in pancreatic β cells prevented diabetes, acute liver failure, and premature death in otherwise PERK-deficient mice, demonstrating that β-cell PERK function is sufficient to prevent the lethal systemic phenotype.[22] These findings show that acute liver failure in PERK-deficient mice, which is the proximate cause of death in humans and mice, is not an obligate cell-autonomous consequence of PERK deficiency in the liver, but can arise secondarily from loss of PERK-dependent pancreatic endocrine function. By contrast, the postnatal necrosis of the exocrine pancreas was shown to be a cell autonomous defect to the acinar cells of the exocrine pancreas.[23] In addition, PERK expression exclusively in pancreatic β cells resulted in restoration of liver-derived IGF-1, catch-up growth, and normalization of bone density.[22] The mechanism by which restoration of PERK function in β cells prevents acute liver failure remains unresolved. However, the findings demonstrate that the physiological consequences of PERK deficiency in a whole organism cannot be inferred from its molecular role in the ER stress response demonstrated in PERK-deficient cultured fibroblasts or solely from cell-autonomous effects observed in individual tissues. The major function of PERK in whole organisms is to regulate insulin synthesis, trafficking, and secretion in pancreatic beta cells for the purpose of maintaining glucose homeostasis and to modulate metabolic homeostasis and growth functions of the liver.[21]

Clinical significance

Patients with mutations in this gene develop Wolcott-Rallison syndrome.[24]

Interactions

EIF2AK3 has been shown to interact with DNAJC3,[25] NFE2L2,[26] and endoplasmic reticulum chaperone BiP (Hsp70).[27]

Inhibitors

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000172071 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031668 – 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. ↑ Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC (December 1998). "Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control". Molecular and Cellular Biology. 18 (12): 7499–7509. doi:10.1128/MCB.18.12.7499. PMC 109330. PMID 9819435.
  6. 1 2 Harding HP, Zhang Y, Ron D (January 1999). "Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase". Nature. 397 (6716): 271–274. Bibcode:1999Natur.397..271H. doi:10.1038/16729. PMID 9930704. S2CID 4416662.
  7. ↑ Hayes SE, Conner LJ, Stramm LE, Shi Y (1999). "Assignment of pancreatic eIF-2alpha kinase (EIF2AK3) to human chromosome band 2p12 by radiation hybrid mapping and in situ hybridization". Cytogenetics and Cell Genetics. 86 (3–4): 327–328. doi:10.1159/000015328. PMID 10575235. S2CID 84483593.
  8. ↑ "Entrez Gene: EIF2AK3 eukaryotic translation initiation factor 2-alpha kinase 3".
  9. ↑ Lee DH, Park JS, Lee YS, Bae SH (2022). "PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway". Redox Biology. 50: 102235. doi:10.1016/j.redox.2022.102235. ISSN 2213-2317. PMC 8801383. PMID 35091323.{{cite journal}}: CS1 maint: article number as page number (link)
  10. ↑ Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology. 23 (20): 7198–7209. doi:10.1128/MCB.23.20.7198-7209.2003. ISSN 0270-7306. PMC 230321. PMID 14517290.
  11. ↑ Bobrovnikova-Marjon E, Pytel D, Riese MJ, Vaites LP, Singh N, Koretzky GA, Witze ES, Diehl JA (2012). "PERK utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate Akt activation, and promote adipocyte differentiation". Molecular and Cellular Biology. 32 (12): 2268–2278. doi:10.1128/MCB.00063-12. ISSN 1098-5549. PMC 3372262. PMID 22493067.
  12. ↑ Sassano ML, van Vliet AR, Vervoort E, Van Eygen S, Van den Haute C, Pavie B, Roels J, Swinnen JV, Spinazzi M, Moens L, Casteels K, Meyts I, Pinton P, Marchi S, Rochin L (2023-03-06). "PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration". The Journal of Cell Biology. 222 (3): e202206008. doi:10.1083/jcb.202206008. ISSN 1540-8140. PMC 9998969. PMID 36821088.{{cite journal}}: CS1 maint: article number as page number (link)
  13. ↑ Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000). "EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome". Nature Genetics. 25 (4): 406–409. doi:10.1038/78085. ISSN 1061-4036. PMID 10932183.
  14. 1 2 Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000). "Perk is essential for translational regulation and cell survival during the unfolded protein response". Molecular Cell. 5 (5): 897–904. doi:10.1016/s1097-2765(00)80330-5. ISSN 1097-2765. PMID 10882126.
  15. 1 2 Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, Gannon M, Ma K, McNaughton K, Cavener DR (2002). "The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas". Molecular and Cellular Biology. 22 (11): 3864–3874. doi:10.1128/MCB.22.11.3864-3874.2002. ISSN 0270-7306. PMC 133833. PMID 11997520.
  16. ↑ Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener DR (2006). "PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis". Cell Metabolism. 4 (6): 491–497. doi:10.1016/j.cmet.2006.11.002. ISSN 1550-4131. PMID 17141632.
  17. ↑ Gupta S, McGrath B, Cavener DR (2010). "PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway". Diabetes. 59 (8): 1937–1947. doi:10.2337/db09-1064. ISSN 1939-327X. PMC 2911049. PMID 20530744.
  18. ↑ Sowers CR, Wang R, Bourne RA, McGrath BC, Hu J, Bevilacqua SC, Paton JC, Paton AW, Collardeau-Frachon S, Nicolino M, Cavener DR (2018-04-06). "The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones". The Journal of Biological Chemistry. 293 (14): 5134–5149. doi:10.1074/jbc.M117.813790. ISSN 1083-351X. PMC 5892574. PMID 29444822.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ↑ Wang R, McGrath BC, Kopp RF, Roe MW, Tang X, Chen G, Cavener DR (2013-11-22). "Insulin secretion and Ca2+ dynamics in β-cells are regulated by PERK (EIF2AK3) in concert with calcineurin". The Journal of Biological Chemistry. 288 (47): 33824–33836. doi:10.1074/jbc.M113.503664. ISSN 1083-351X. PMC 3837125. PMID 24114838.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  20. ↑ Wang R, Munoz EE, Zhu S, McGrath BC, Cavener DR (2014). "Perk gene dosage regulates glucose homeostasis by modulating pancreatic β-cell functions". PloS One. 9 (6): e99684. doi:10.1371/journal.pone.0099684. ISSN 1932-6203. PMC 4051701. PMID 24915520.{{cite journal}}: CS1 maint: article number as page number (link) CS1 maint: unflagged free DOI (link)
  21. 1 2 Cavener DR, Gupta S, McGrath BC (2010). "PERK in beta cell biology and insulin biogenesis". Trends in endocrinology and metabolism: TEM. 21 (12): 714–721. doi:10.1016/j.tem.2010.08.005. ISSN 1879-3061. PMC 2991375. PMID 20850340.
  22. 1 2 Li Y, Iida K, O'Neil J, Zhang P, Li S, Frank A, Gabai A, Zambito F, Liang SH, Rosen CJ, Cavener DR (2003). "PERK eIF2alpha kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver". Endocrinology. 144 (8): 3505–3513. doi:10.1210/en.2003-0236. ISSN 0013-7227. PMID 12865332.
  23. ↑ Iida K, Li Y, McGrath BC, Frank A, Cavener DR (2007-08-29). "PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice". BMC cell biology. 8: 38. doi:10.1186/1471-2121-8-38. ISSN 1471-2121. PMC 2072952. PMID 17727724.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ↑ Søvik O, Njølstad PR, Jellum E, Molven A (December 2008). "Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome". Journal of Inherited Metabolic Disease. 31 (Suppl 2): S293–S297. doi:10.1007/s10545-008-0866-1. PMID 18500571. S2CID 1751676.
  25. ↑ Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG (December 2002). "Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK". Proceedings of the National Academy of Sciences of the United States of America. 99 (25): 15920–15925. Bibcode:2002PNAS...9915920Y. doi:10.1073/pnas.252341799. PMC 138540. PMID 12446838.
  26. ↑ Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (October 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology. 23 (20): 7198–7209. doi:10.1128/MCB.23.20.7198-7209.2003. PMC 230321. PMID 14517290.
  27. ↑ Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (June 2000). "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response". Nature Cell Biology. 2 (6): 326–332. doi:10.1038/35014014. PMID 10854322. S2CID 22684712.

Further reading

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