Phospholamban is degraded through ubiquitin‐proteasome pathway by pVHL in failing hearts

Abstract

The ubiquitin‐proteasome system (UPS) plays an essential and pivotal role for intracellular protein degradation and protein homeostasis. The von Hippel‐Lindau (VHL) is a tumor suppressor that forms E3 ubiquitin ligase complex, which negatively regulates the hypoxia‐inducible factor‐1a (HIF‐1a) by promoting its polyubiquitination. Although it is reported that protein VHL (pVHL) is involved in the stabilization of heart function via HIF1‐a regulation, the role of pVHL in UPS‐mediated protein degradation in the heart is not fully understood. Here, we show that phospholamban (PLN), which acts as a negative inhibitor of sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA2a), was co‐immunoprecipitated with pVHL in both PLN‐overexpressing HEK293 cells and mouse hearts with dilated cardiomyopathy (transgenic mice expressing an Arg9 to Cys point mutation in PLN, TgPLNR9C mice). Furthermore, the overexpression of VHL into HEK293 cells decreased PLN expression levels under the H2O2 stress condition, whereas knockdown of VHL by transient transfection with VHL‐siRNA increased PLN expression level both under the normal and the H2O2 stress conditions. Taken together with our previous study in which we showed that PLN is ubiquitinated at Lys3 residue, and polyubiquitination of PLN was significantly increased with its lower expression in TgPLNR9C mice compared to control, we propose that increased oxidative stress may increase the binding of pVHL with PLN to induce its degradation in failing hearts.