p97 is a AAA-ATPase that plays critical roles in a myriad of cellular protein quality control processes, including the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway that targets misfolded proteins in the ER for degradation in the cytosol by the ubiquitin proteasome system. Mutations in p97 cause a multisystem degenerative proteinopathy disorder called inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) that includes pathologies of the nervous system, skeletal muscle, bone, and heart. Previous studies in the laboratory into the mechanisms whereby thrombospondin 4 has its cardioprotective effects and enhanced ERAD activity identified p97 as a direct interacting partner. This observation suggested that p97 itself could be an important cardioprotective effector by benefiting protein quality control in the heart. To address this hypothesis here we generated cardiac-specific transgenic mice overexpressing wildtype p97 or a p97
K524A
mutant with deficient ATPase activity, the latter of which functioned as a dominant negative. Mice overexpressing wildtype p97 exhibit normal cardiac structure and function while mutant p97 overexpressing mice develop cardiomyopathy, upregulate several ERAD complex components, and have elevated levels of ubiquitinated proteins. Proteomics and immunoprecipitation assays identified overwhelming interactions between endogenous p97 and a number of interesting protein complexes that suggest unique functions for this protein in regulating protein quality control in the heart. The results and novel regulatory relationships will be presented, which suggests entirely unique pathways whereby p97 functions in the heart.
Translational Regulation of Pmt1 and Pmt2 by Bfr1 Affects Unfolded Protein O-Mannosylation