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. PageJonathan C. Schisler, David A. Kass

研究成果: Contribution to journalArticle査読

6 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号5237
ジャーナルNature communications
11
1
DOI
出版ステータス出版済み - 12 1 2020
外部発表はい

All Science Journal Classification (ASJC) codes

  • 化学 (全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 物理学および天文学(全般)

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