EIF2AK3

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.