CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury
| العنوان: | CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury |
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| المؤلفون: | 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 |
| المصدر: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-12 (2020) |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b0da9f09773c6c255e955440f56caa0eTest https://doi.org/10.1038/s41467-020-18980-xTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b0da9f09773c6c255e955440f56caa0e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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