Genetic knock-in of EIF2AK3 variants reveals differences in PERK activity in mouse liver and pancreas under endoplasmic reticulum stress

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School of Dental Medicine::Departmental Papers (Dental)
Degree type
Discipline
Dentistry
Subject
EIF2AK3
Endoplasmic reticulum
Haplotype
Protein kinase RNA-like ER kinase
Single-nucleotide variant
Stress
Unfolded protein response
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2024-12
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Ghura, Shivesh
Beratan, Noah R.
Shi, Xinglong
Alvarez-Periel, Elena
Bond Newton, Sarah E.
Akay-Espinoza, Cagla
Jordan-Sciutto, Kelly L.
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Abstract

Common single-nucleotide variants (SNVs) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) slightly increase the risk of disorders in the periphery and the central nervous system. EIF2AK3 encodes protein kinase RNA-like endoplasmic reticulum kinase (PERK), a key regulator of ER stress. Three exonic EIF2AK3 SNVs form the PERK-B haplotype, which is present in 28% of the global population. Importantly, the precise impact of these SNVs on PERK activity remains elusive. In this study, we demonstrate that PERK-B SNVs do not alter PERK expression or basal activity in vitro and in the novel triple knock-in mice expressing the exonic PERK-B SNVs in vivo. However, the kinase activity of PERK-B protein is higher than that of PERK-A in a cell-free assay and in mouse liver homogenates. Pancreatic tissue in PERK-B/B mice also exhibit increased susceptibility to apoptosis under acute ER stress. Monocyte-derived macrophages from PERK-B/B mice exhibit higher PERK activity than those from PERK-A/A mice, albeit with minimal functional consequences at acute timepoints. The subtle PERK-B-driven effects observed in liver and pancreas during acute stress implicate PERK as a contributor to disease susceptibility. The novel PERK-B mouse model provides valuable insights into ER stress-induced PERK activity, aiding the understanding of the genetic basis of disorders associated with ER stress.

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2024-12
Journal title
Scientific Reports
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Nature
Publisher DOI
10.1038/s41598-024-74362-z
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