Biology:EIF2AK3

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Short description: Human protein and coding gene

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2][3][4]

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.[2] PERK also has other phosphorylation substrates and has functions in regulating mitochondrial homeostasis that are independent of its kinase activity.[5][6][7][8] Because of this functional complexity, the biochemical mechanisms underlying the diverse defects observed in PERK-deficient humans and mice remain unclear.

Clinical significance

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.[9][10][11]

Animal studies

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.[10][11] 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.[12] 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.[13][14] 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.[15][16][17] 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.[18] 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.[19] 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.[18] 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.[17]

Clinical significance

Patients with mutations in this gene develop Wolcott-Rallison syndrome.[20]

Interactions

EIF2AK3 has been shown to interact with DNAJC3,[21] NFE2L2,[6] and endoplasmic reticulum chaperone BiP (Hsp70).[22]

Inhibitors

References

  1. ↑ "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. December 1998. doi:10.1128/MCB.18.12.7499. PMID 9819435. 
  2. ↑ 2.0 2.1 "Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase". Nature 397 (6716): 271–274. January 1999. doi:10.1038/16729. PMID 9930704. Bibcode: 1999Natur.397..271H. 
  3. ↑ "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. 1999. doi:10.1159/000015328. PMID 10575235. 
  4. ↑ "Entrez Gene: EIF2AK3 eukaryotic translation initiation factor 2-alpha kinase 3". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=9451. 
  5. ↑ "PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway". Redox Biology 50. April 2022. doi:10.1016/j.redox.2022.102235. PMID 35091323. 
  6. ↑ 6.0 6.1 "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology 23 (20): 7198–7209. October 2003. doi:10.1128/MCB.23.20.7198-7209.2003. PMID 14517290. Bibcode: 2003MolCB..23.7198C. 
  7. ↑ "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. June 2012. doi:10.1128/MCB.00063-12. PMID 22493067. 
  8. ↑ "PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration". The Journal of Cell Biology 222 (3). March 2023. doi:10.1083/jcb.202206008. PMID 36821088. 
  9. ↑ "EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome". Nature Genetics 25 (4): 406–409. August 2000. doi:10.1038/78085. PMID 10932183. 
  10. ↑ 10.0 10.1 "Perk is essential for translational regulation and cell survival during the unfolded protein response". Molecular Cell 5 (5): 897–904. May 2000. doi:10.1016/s1097-2765(00)80330-5. PMID 10882126. 
  11. ↑ 11.0 11.1 "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. June 2002. doi:10.1128/MCB.22.11.3864-3874.2002. PMID 11997520. 
  12. ↑ "PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis". Cell Metabolism 4 (6): 491–497. December 2006. doi:10.1016/j.cmet.2006.11.002. PMID 17141632. 
  13. ↑ "PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway". Diabetes 59 (8): 1937–1947. August 2010. doi:10.2337/db09-1064. PMID 20530744. 
  14. ↑ "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. April 2018. doi:10.1074/jbc.M117.813790. PMID 29444822. 
  15. ↑ "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. November 2013. doi:10.1074/jbc.M113.503664. PMID 24114838. 
  16. ↑ "Perk gene dosage regulates glucose homeostasis by modulating pancreatic β-cell functions". PLOS ONE 9 (6). 2014. doi:10.1371/journal.pone.0099684. PMID 24915520. Bibcode: 2014PLoSO...999684W. 
  17. ↑ 17.0 17.1 "PERK in beta cell biology and insulin biogenesis". Trends in Endocrinology and Metabolism 21 (12): 714–721. December 2010. doi:10.1016/j.tem.2010.08.005. PMID 20850340. 
  18. ↑ 18.0 18.1 "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. August 2003. doi:10.1210/en.2003-0236. PMID 12865332. 
  19. ↑ "PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice". BMC Cell Biology 8 (1). August 2007. doi:10.1186/1471-2121-8-38. PMID 17727724. 
  20. ↑ "Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome". Journal of Inherited Metabolic Disease 31 (Suppl 2): S293–S297. December 2008. doi:10.1007/s10545-008-0866-1. PMID 18500571. 
  21. ↑ "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. December 2002. doi:10.1073/pnas.252341799. PMID 12446838. Bibcode: 2002PNAS...9915920Y. 
  22. ↑ "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response". Nature Cell Biology 2 (6): 326–332. June 2000. doi:10.1038/35014014. PMID 10854322. 

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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