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. Page, Jonathan C. Schisler and David A. Kass ()
Additional contact information
Mark J. Ranek: Johns Hopkins Medical Institutions
Christian Oeing: Johns Hopkins Medical Institutions
Rebekah Sanchez-Hodge: McAllister Heart Institute, The University of North Carolina at Chapel Hill
Kristen M. Kokkonen-Simon: Johns Hopkins Medical Institutions
Danielle Dillard: Johns Hopkins Medical Institutions
M. Imran Aslam: Johns Hopkins Medical Institutions
Peter P. Rainer: Johns Hopkins Medical Institutions
Sumita Mishra: Johns Hopkins Medical Institutions
Brittany Dunkerly-Eyring: Johns Hopkins Medical Institutions
Ronald J. Holewinski: Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute
Cornelia Virus: McAllister Heart Institute, The University of North Carolina at Chapel Hill
Huaqun Zhang: Miami University
Matthew M. Mannion: Miami University
Vineet Agrawal: Johns Hopkins Medical Institutions
Virginia Hahn: Johns Hopkins Medical Institutions
Dong I. Lee: Johns Hopkins Medical Institutions
Masayuki Sasaki: Johns Hopkins Medical Institutions
Jennifer E. Van Eyk: Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute
Monte S. Willis: McAllister Heart Institute, The University of North Carolina at Chapel Hill
Richard C. Page: Miami University
Jonathan C. Schisler: McAllister Heart Institute, The University of North Carolina at Chapel Hill
David A. Kass: Johns Hopkins Medical Institutions

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18980-x

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