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. Becky Sanchez, Research Associate in the Schisler Lab, is coauthor. This paper also featured services provided by our Proteomics Core headed by Laura Herring and Lee Graves.
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,. It was published October 20, 2020 in Nature Communications.
Abstract
“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.}”
Novel Therapeutic Opportunities
“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. 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. 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. While PKG activation has historically been leveraged for its vasodilator capacity, the present data reveal its role in PQC by enhancing CHIP functionality. Both PKG and CHIP are widely expressed in many cell types, including the brain and cancer cells, and thus we believe the current findings will likely apply to the heart as well as other tissues, providing novel therapeutic opportunities.”
~The above excerpts are from the Nature Communications article published October 20, 2020.