CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury

Mark J. Ranek, Christian Oeing, Rebekah Sanchez-Hodge, Kristen M. Kokkonen-Simon, Danielle Dillard, M. Imran Aslam, Peter P. Rainer, Sumita Mishra, Brittany Dunkerly-Eyring, Ronald J. Holewinski, Cornelia Virus, Huaqun Zhang, Matthew M. Mannion, Vineet Agrawal, Virginia Hahn, Dong I. Lee, Masayuki Sasaki, Jennifer E. Van Eyk, Monte S. Willis, Richard C. PageJonathan C. Schisler, David A. Kass

Research output: Contribution to journalArticlepeer-review

Abstract

Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.

Original languageEnglish
Article number5237
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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