Chen et al. (2012) illustrated that the loss of E3 ligase activity promoted the impaired protein degradation in hypertrophic cardiomyopathy. Xu et al. (2020) reported that the ubiquitin-conjugating enzyme E2 variant 1 (Ube2v1) positively regulated protein aggregation by modulating UPS in cardiomyocytes, partially by enhancing K63 ubiquitination during a proteotoxic stimulus, supporting the hypothesis that UPS-mediated proteotoxic intracellular protein aggregation and degradation may lead to the progression of cardiac disease. The gene discussed is UBE2V1; the disease is hypertrophic cardiomyopathy.