CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury
| Autor: | Brittany Dunkerly-Eyring, Danielle Dillard, Masayuki Sasaki, Peter P. Rainer, Kristen M. Kokkonen-Simon, David A. Kass, Sumita Mishra, Richard C. Page, Jennifer E. Van Eyk, Virginia S. Hahn, Matthew M. Mannion, Huaqun Zhang, Christian U. Oeing, M. Imran Aslam, Mark J. Ranek, Ronald J. Holewinski, Jonathan C. Schisler, Dong I. Lee, Cornelia Virus, Monte S. Willis, Rebekah Sanchez-Hodge, Vineet Agrawal |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Science Ubiquitin-Protein Ligases Amino Acid Motifs General Physics and Astronomy macromolecular substances Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Ischemia Cyclic GMP-Dependent Protein Kinases Animals Humans Phosphorylation lcsh:Science Multidisciplinary biology Chemistry Myocardium Protein turnover Heart General Chemistry Cell biology Myocardial infarction Mechanisms of disease 030104 developmental biology Proteostasis Proteasome Proteotoxicity Chaperone (protein) cardiovascular system biology.protein lcsh:Q Female cGMP-dependent protein kinase 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-12 (2020) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-18980-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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