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

Autor: Ghura S; Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA., Beratan NR; Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA., Shi X; Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA., Alvarez-Periel E; Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA., Bond Newton SE; Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA.; Department of Neuroscience, Weinberg ALS Center, Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Akay-Espinoza C; Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA., Jordan-Sciutto KL; Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA. jordank@upenn.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 11; Vol. 14 (1), pp. 23812. Date of Electronic Publication: 2024 Oct 11.
DOI: 10.1038/s41598-024-74362-z
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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