Abstract 11876: The Selenoprotein, Vimp, Selectively Regulates a Newly Defined Non-Canonical Form of Proteasomal Degradation at the ER to Modulate Cardiac Hypertrophy

Abstract

Introduction: Canonical endoplasmic reticulum (ER) associated degradation (ERAD) adaptively degrades misfolded potentially toxic ER proteins that can accumulate in cells under a variety of stresses. However, roles for ERAD in vivo in potentially pathological conditions have not been well studied. Hypothesis: Here, we examined a functional component of ERAD, VCP-interacting membrane protein (VIMP), positing that decreasing VIMP would decrease canonical ERAD, which would be maladaptive in a mouse model of pathological cardiac hypertrophy. Methods: Mice were injected with AAV9 to transduce cardiomyocytes with either a shRNA targeting VIMP (shVIMP), or ectopic wild-type or an ERAD-deficient AAV-FLAGVIMP and subjected to pressure overload-induced cardiac hypertrophy. Mice were also injected with a novel AAV expressing a canonical ERAD substrate to monitor the rate of ERAD in vivo for the first time in any organ system. Results: Unexpectedly, both VIMP knockdown and overexpression in mouse hearts decreased canonical ERAD while only VIMP knockdown adaptively decreased pathological cardiac hypertrophy. We evaluated the effects of VIMP gain and loss of function on ERAD-mediated degradation of a cytosolic pro-growth kinase, serum/glucocorticoid-regulated kinase 1, SGK1, which we showed here to contribute to pathological cardiac hypertrophy and to be a non-canonical, i.e non-ER localized substrate for ERAD. In contrast to its effect on canonical ERAD, VIMP overexpression decreased noncanonical ERAD-mediated degradation of SGK1, which accounted for the maladaptive effects of increased VIMP in the heart. We found that DERLIN1 was responsible for increasing ERAD-mediated SGK1 degradation, which accounted for the suppression of pathological cardiac hypertrophy when VIMP was knocked down. Conclusions: Thus, the relative levels of VIMP and DERLIN1 comprise a molecular switch mechanism that regulates a newly defined non-canonical ERAD-mediated degradation of SGK1, a critical signaling kinase contributing to pathological cardiac hypertrophy. Furthermore, this noncanonical ERAD is of unique importance in cardiomyocytes as these effects of VIMP gain and loss of function were not observed in cardiac fibroblasts from the same mouse hearts.