Protein quality control is vital for cellular function, encompassing pathways that help proteins fold and maintain structural conformations, as well as cellular systems that ultimately degrade proteins. Several degenerative diseases, including those that are accompanied by abnormal aging, are associated with altered protein quality control, highlighting the importance of protein fidelity in both health and disease. CHIP (carboxyl terminus of heat shock 70-interacting protein) is a multi- functional enzyme with distinct activities that contribute both to protein folding and protein degradation. Our lab recently identified the first human disease associated with CHIP mutations, with phenotypes that include accelerated aging, cerebellar ataxia and degeneration, cognitive dysfunction, and hypogonadism. Two known CHIP substrates, receptor- interacting protein kinase 3 (RIPK3) and AMP-activated kinase (AMPK), are regulated by either the degradative or re- folding activities of CHIP, respectively. These kinases regulate important cellular processes, necroptosis (an inflammatory form of programmed cell death) and cellular metabolism, both of which are central to the ability of cells to react to the stress that occurs with aging or in pathophysiological conditions. In this proposal, we seek to define the role of protein quality control in aging by determining how the various activities of CHIP regulate these recently identified substrates, and the mechanism that drives the sensitivity to cell stress when CHIP function is compromised. Our approach includes novel pre-clinical models of accelerated aging, cutting-edge cell models, and determining the molecular movements of CHIP when engaged with its substrate. We then ask how disease-causing mutations in CHIP mechanistically drive the molecular and cellular phenotypes associated with CHIP dysfunction. Finally, we will use our preclinical models to determine how aging and disease pathologies are altered when necroptosis is inhibited pharmacologically, or when CHIP function is restored genetically. The ultimate goal of these studies is to identify druggable targets of CHIP-regulated signaling pathways that impact age-dependent progression of degenerative conditions.
CHIP is a key enzyme in cellular protein quality control. On a cellular level, altered CHIP function sensitizes cells to stress, and at an organismal level, the inability to respond to stress results in degenerative pathologies and accelerated aging. Our overall goal is to determine the mechanisms and dysfunction caused by disease-causing CHIP mutations at the atomic, cellular, and whole-body level. We will use novel cell systems in combination with our preclinical models to test novel therapies to counteract the loss of CHIP function. In doing so, we will establish a new framework to better understand this aging and CHIP biology that, in turn, will allow us to develop precision medicine approaches to alleviate degeneration caused by the loss of CHIP function.
