Ubiquitin receptors and cardiac proteotoxicity

University Of South Dakota, Vermillion SD

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Abstract

DESCRIPTION (provided by applicant): Increased levels of misfolded proteins in the heart are associated with a large subset of congestive heart failure (CHF), the final common pathway for virtually all heart diseases and afflicting the life of millions of Americans. Targeted removal of most cellular proteins is primarily done by the ubiquitin-proteasome system (UPS) which degrades a protein via two steps: (1) attachment of a chain of ubiquitin (Ub) to a target protein molecule via a process known as ubiquitination; (2) degradation of the ubiquitinated protein by the proteasome. Cardiac UPS dysfunction is associated with CHF of common causes and a frequently indicated defect is an uncoupling between the two steps, as suggested by the paradoxical co-existence of increased levels of ubiquitinated proteins with elevated or normal proteasomal peptidase activities in diseased myocardium. However, little is known about the molecular basis and pathophysiological significance of the uncoupling. The UBL-UBA family of Ub receptors (Ubiquilin1, Rad23, Ddi1) are purport to recruit ubiquitinated proteins for the proteasome, thereby promoting the coupling. To date, the role of none of these Ub receptors in mammalian hearts is elucidated. Our pilot studies reveal that cardiac Ubqln1 proteins were remarkably increased in human end-stage CHF from ischemic heart disease or dilated cardiomyopathy and in mouse models of desmin-related cardiomyopathy (DRC), a bona fide cardiomyopathy caused by increased expression of misfolded proteins. Our preliminary data also suggest that Ubqln1 promotes proteasomal degradation of ubiquitinated misfolded proteins without altering proteasome activities. Hence, we hypothesize that Ubqln1 up-regulation protects against proteotoxicity in cardiomyocytes by enhancing the recruitment of ubiquitinated misfolded proteins to the proteasome for degradation. A unique set of genetically altered mice as well as human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes will be used to interrogate Ubqln1 and proteasome functions in cardiomyocytes to investigate the role of Ubqln1 in the DRC progression, myocardial ischemia/reperfusion (I/R) injury and post I/R cardiac remodeling in mice and to test the hypothesis that Ubqln1 functions as a shuttling Ub receptor to recruit ubiquitinated misfolded proteins to the proteasome for degradation, thereby protecting against proteotoxicity in cardiomyocytes. The completion of this work is expected to improve our understanding of cardiac protein quality control and provide new molecular targets for developing new strategies to fight cardiac disease with increased proteotoxicity, an increasingly suggested major pathogenic factor of CHF.