Journal article
ER stress tolerance is regulated by copper-dependent PERK kinase activity
Cell reports (Cambridge), v 44(10), 116318
25 Sep 2025
PMID: 41014556
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Pancreatic/PKR-like endoplasmic reticulum (ER) kinase (PERK) is a kinase that, in response to ER stress, mediates dual homeostatic and pro-apoptotic signaling. Thus, intricate regulation is required for physiological function. Attempts to modulate PERK activity have shown that the determinants of adaptive vs. maladaptive signaling remain ambiguous. Here, with purified protein, we provide evidence that PERK binds copper, identifies residues required for interaction, and demonstrates that copper is necessary for kinase activity. Furthermore, cellular PERK activity can be modulated via copper availability, and this regulatory relationship can be manipulated to dictate ER stress tolerance. Critically, these phenomena translate to phenotypes in vivo, as C. elegans harboring a "PERK-copper mutant" exhibit exacerbated ER-stress sensitivity. The copper-PERK paradigm suggests that copper homeostasis, as a regulator of PERK, may constitute a critical factor in resolving the long-standing ambiguity in endeavors to therapeutically target PERK.
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Details
- Title
- ER stress tolerance is regulated by copper-dependent PERK kinase activity
- Creators
- Sarah E Bond Newton (Corresponding Author)Xinglong Shi - University of PennsylvaniaNoah R Beratan - University of PennsylvaniaJulia Perhacs - Drexel UniversityJitendra K Arya - University of PennsylvaniaMargaret K Bond - University of PennsylvaniaTali Gidalevitz - Drexel UniversityCagla Akay-Espinoza - University of PennsylvaniaDonita C Brady - University of PennsylvaniaKelly L Jordan-Sciutto - University of Pennsylvania
- Publication Details
- Cell reports (Cambridge), v 44(10), 116318
- Publisher
- Elsevier
- Number of pages
- 22
- Grant note
- NIH/NIMH: R01MH109382 NIH: T32GM008275 University of Pennsylvania BGS Training Grant
This work was funded by the NIH/NIMH R01MH109382 (K.L.J.-S.) , the NIH T32GM008275 Structural Biology and Molecular Biophysics Training Grant (S.E.B.N.) , and the University of Pennsylvania BGS Training Grant (S.E.B.N.) . A special thanks to the Koumenis lab at the University of Pennsylvania for providing WT and KO PERK MEFs; the Brady lab at the University of Pennsylvania for providing CTR1-, KO CTR1, ATP7A +/+ , and ATP7A-/- MEFs; and the Gidalevitz lab at Drexel University and InVivo Biosystems for providing the C . elegans strains. Adam Yates, Ph.D. of the Children's Hospital of Pennsylvania Biostatistics and Data Management Core consulted on statistical analyses. Sequencing was completed by the Department of Genetics at the University of Pennsylvania.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:001584777600001
- Scopus ID
- 2-s2.0-105017881497
- Other Identifier
- 991022118549704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology