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.
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. PERK also has other phosphorylation substrates and has functions in regulating mitochondrial homeostasis that are independent of its kinase activity. 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.
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. 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. 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. 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. 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. 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. 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. 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.
Clinical significance
Patients with mutations in this gene develop Wolcott-Rallison syndrome.
Interactions
EIF2AK3 has been shown to interact with DNAJC3, NFE2L2, and endoplasmic reticulum chaperone BiP (Hsp70).
Inhibitors GSK2606414 3-Fluoro-GSK2606414
References
Further reading