Sumo E2 enzyme UBC9 is required for efficient protein quality control in cardiomyocytes

Manish K. Gupta, James Gulick, Ruijie Liu, Xuejun Wang, Jeffery D. Molkentin, Jeffrey Robbins

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Rationale: Impairment of proteasomal function is pathogenic in several cardiac proteinopathies and can eventually lead to heart failure. Loss of proteasomal activity often results in the accumulation of large protein aggregates. The ubiquitin proteasome system (UPS) is primarily responsible for cellular protein degradation, and although the role of ubiquitination in this process is well studied, the function of an ancillary post-translational modification, SUMOylation, in protein quality control is not fully understood. Objective: To determine the role of ubiquitin-conjugating enzyme 9 (UBC9), a small ubiquitin-like modifier' conjugating enzyme, in cardiomyocyte protein quality control. Methods and Results: Gain- and loss-of-function approaches were used to determine the importance of UBC9. Overexpression of UBC9 enhanced UPS function in cardiomyocytes, whereas knockdown of UBC9 by small interfering RNA caused significant accumulations of aggregated protein. UPS function and relative activity was analyzed using a UPS reporter protein consisting of a short degron, CL1, fused to the COOH-terminus of green fluorescent protein (GFPu). Subsequently, the effects of UBC9 on UPS function were tested in a proteotoxic model of desmin-related cardiomyopathy, caused by cardiomyocyte-specific expression of a mutated 'B crystallin, CryABR120G. CryABR120G expression leads to aggregate formation and decreased proteasomal function. Coinfection of UBC9-adenovirus with CryABR120G virus reduced the proteotoxic sequelae, decreasing overall aggregate concentrations. Conversely, knockdown of UBC9 significantly decreased UPS function in the model and resulted in increased aggregate levels. Conclusions: UBC9 plays a significant role in cardiomyocyte protein quality control, and its activity can be exploited to reduce toxic levels of misfolded or aggregated proteins in cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)721-729
Number of pages9
JournalCirculation Research
Volume115
Issue number8
DOIs
StatePublished - 2014

Keywords

  • Autophagy
  • Cardiomyopathies
  • Proteasome endopeptidase complex

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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