The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones

Carrie R. Sowers, Rong Wang, Rebecca A. Bourne, Barbara C. McGrath, Jingjie Hu, Sarah C. Bevilacqua, James C. Paton, Adrienne W. Paton, Sophie Collardeau-Frachon, Marc Nicolino, Douglas R. Cavener

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Loss-of-function mutations of the protein kinase PERK (EIF2AK3) in humans and mice cause permanent neonatal diabetes and severe proinsulin aggregation in the endoplasmic reticulum (ER), highlighting the essential role of PERK in insulin production in pancreatic cells. As PERK is generally known as a translational regulator of the unfolded protein response (UPR), the underlying cause of these cell defects has often been attributed to derepression of proinsulin synthesis, resulting in proinsulin overload in the ER. Using high-resolution imaging and standard protein fractionation and immunological methods we have examined the PERK-dependent phenotype more closely. We found that whereas proinsulin aggregation requires new protein synthesis, global protein and proinsulin synthesis are down-regulated in PERK-inhibited cells, strongly arguing against proinsulin overproduction being the root cause of their aberrant ER phenotype. Furthermore, we show that PERK regulates proinsulin proteostasis by modulating ER chaperones, including BiP and ERp72. Transgenic overexpression of BiP and BiP knockdown (KD) both promoted proinsulin aggregation, whereas ERp72 overexpression and knockdown rescued it. These findings underscore the importance of ER chaperones working in concert to achieve control of insulin production and identify a role for PERK in maintaining a functional balance among these chaperones.

Original languageEnglish (US)
Pages (from-to)5134-5149
Number of pages16
JournalJournal of Biological Chemistry
Volume293
Issue number14
DOIs
StatePublished - Apr 6 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Sowers, C. R., Wang, R., Bourne, R. A., McGrath, B. C., Hu, J., Bevilacqua, S. C., Paton, J. C., Paton, A. W., Collardeau-Frachon, S., Nicolino, M., & Cavener, D. R. (2018). The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones. Journal of Biological Chemistry, 293(14), 5134-5149. https://doi.org/10.1074/jbc.M117.813790