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

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.

SUBMITTER: Ranek MJ

PROVIDER: S-EPMC7575552 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Ranek Mark J MJ Oeing Christian C Sanchez-Hodge Rebekah R Kokkonen-Simon Kristen M KM Dillard Danielle D Aslam M Imran MI Rainer Peter P PP Mishra Sumita S Dunkerly-Eyring Brittany B Holewinski Ronald J RJ Virus Cornelia C Zhang Huaqun H Mannion Matthew M MM Agrawal Vineet V Hahn Virginia V Lee Dong I DI Sasaki Masayuki M Van Eyk Jennifer E JE Willis Monte S MS Page Richard C RC Schisler Jonathan C JC Kass David A DA

Nature communications 20201020 1

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 marked ...[more]

PMID: 33082318

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

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

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