Heart failure (HF) is a leading cause of human mortality and morbidity. The long term goal of this project is to help delineate cellular and molecular mechanisms by which primary heart diseases progress to HF, helping devise new strategies to prevent or better treat HF. Protein degradation by the ubiquitin-proteasome system (UPS) and autophagy is pivotal to protein quantity and quality control (PQQC). Cardiac PQQC dysfunction can cause cardiomyocyte (CM) death. Increases in CM apoptosis and regulated necrosis contribute to HF but mechanisms underlying CM regulated necrosis is poorly understood. The RIP1-RIP3 pathway is shown to mediate CM necroptosis, a newly identified major form of regulated necrosis that was recently implicated in maladaptive cardiac remodeling and HF. However, the molecular link between pathological insults and the activation of the RIP1-RIP3 pathway in the heart remains obscure. The COP9 signalosome (CSN) is a ubiquitously expressed protein complex consisting of 8 unique protein subunits (CSN1 ~ CSN8). Its bona fide biochemical activity is cullin deneddylation, essential to the catalytic dynamics of a large family of ubiquitin ligases. Individual CSN subunits or CSN mini-complexes may also control gene expression beyond regulation of protein stability. We discovered that CSN8/CSN regulates both UPS and autophagy in mouse hearts and that CM-restricted CSN8 knockout (CSN8CKO) caused massive CM necrosis, dilated cardio- myopathy, and mouse premature death. The CM necrosis in CSN8CKO mice turns out being exclusively necroptosis mediated by the RIP1-RIP3 pathway, rendering CSN8CKO mice an invaluable model for studying CM necroptosis. Upon CSN8 depletion, mouse hearts display marked upregulation of protein kinase C? (PKC?). PKC? was previously shown to promote CM death, including necrosis, in stressed myocardium but has not been mechanistically linked to CM necroptosis. Our pilot data strongly support a critical role for PKC? in linking CSN8CKO to the RIP1-RIP3 necroptotic pathway. Hence, using cutting-edge technologies, this project will test the central hypothesis that CSN8 suppresses CM necroptosis by both supporting cullin-deneddylation and repressing PKC? gene expression. This is aimed to (1) determine the role of cullin deneddylation in suppressing CM necroptosis, (2) define the role of PKC? upregulation in CM necroptosis, and (3) dissect the relationships among CSN8/CSN, PKC? and the RIP3-centered necroptotic pathway. This will yield novel mechanistic insights into the molecular pathway to CM necroptosis and CSN physiological functions.
Congestive heart failure is the final common pathway of virtually all heart disease and is the most expensive single diagnosis in US health care. It is a highly lethal and disabling syndrome. Despite recent advances in its clinical management, it remains the leading cause of death in the US. This research project will help improve our understanding on the molecular mechanisms underlying the progression of various heart diseases to congestive heart failure, which will ultimately facilitate the search for new measures to prevent or more effectively treat this common and yet life-threatening disorder.
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