![]() While PKG activation has historically been leveraged for its vasodilator capacity, the present data reveal its role in PQC by enhancing CHIP functionality. All of these targets have existing small molecules or peptides in clinical use and/or under active studies in humans with cardiac or neurological disease. Clinically used agents include nitric oxide donors, organic nitrates, soluble guanylate cyclase stimulators, and PDE5 inhibitors that enhance NO-dependent cGMP synthesis, and natriuretic peptides (NP), neprilysin inhibitors, and PDE9 inhibitors that increase NP-dependent cGMP stimulation. “The intersection of PKG signaling with enhanced CHIP functionality is important, since from a clinical perspective, it suggests new therapeutic targets suitable for an array of existing and developing PKG activation strategies. PKG activation provides post-translational enhancement of protein quality control via CHIP.}” Novel Therapeutic Opportunities CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. 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). While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. ![]() 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. “Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. It was published Octoin Nature Communications. The article by Jonathan Schisler, PhD, Assistant Professor in the Pharmacology Department and member of the UNC McAllister Heart Institute, is a collaboration with Kass Labs at Johns Hopkins University, titled “CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury. This paper also featured services provided by our Proteomics Core headed by Laura Herringand Lee Graves. Becky Sanchez, Research Associate in the Schisler Lab, is coauthor. Check out Jonathan Schisler’s Nature Communications paper detailing how the cardioprotective effects of protein kinase G are mediated by the protein quality control enzyme CHIP, reducing proteotoxicity in heart failure.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |