Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-18980-x
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Funding
- NIH-NHLBI [HL-135827, HL-119012, HL-093432, HHSN268201000032C]
- Fondation Leducq TransAtlantic Network of Excellence
- Peter Belfour Laboratory
- American Heart Association Mid-Atlantic Fellowship Grant
- SDG [16SDG26960000]
- CDA [18CDA34110140]
- Amyloidosis Foundation Donald C. Brockman Memorial Research Grant
- Max Kade Fellowship by the Austrian Academy of Sciences
- NIH [F31-HL134196, F31-HL HL143905, NIH-NIA-AG-061188]
- NIH-NIGMS [GM-R35128595]
- NSF MCB [1552113]
- Miami University through the Robert H. and Nancy J. Blayney Professorship
- [NHLBI-T32-HL-07227]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1552113] Funding Source: National Science Foundation
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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. Carboxyl terminus of Hsc70-interacting protein (CHIP) is proteostasis regulator. Here the authors show that CHIP-mediated protein turnover is enhanced by PKG-mediated phosphorylation, which results in attenuated cardiac ischemic proteotoxicity.
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