The reactive oxygen species (ROS) are important signaling molecules that contribute to etiology of multiple muscle-related diseases, including cardiomyopathy and heart failure. However, it remains yet incompletely understood how ROS or cellular stress make an impact on structural stability of sarcomere or myofibril, a contractile unit of muscle. Protein glutathionylation is one of major protein cysteine oxidative modifications that play an important role in redox signaling and oxidative stress. In this report, we used a clickable glutathione approach in cardiomyocytes, finding that SET and MYND Domain Containing 2 (SMYD2), a lysine methyltransferase, can be selectively glutathionylated at C13 residue. Functional studies showed that SMYD2 C13 glutathionylation serve as a key molecular event that leads to a loss of myofibril integrity and degradation of sarcomeric proteins mediated by matrix metalloprotease 2 (MMP-2) and calpain 1. Biochemical analysis demonstrated that SMYD2 glutathionylated at a C13 residue loses its interaction with Hsp90 and N2A, a domain of titin that is important for stress-sensing. Further analysis showed that N2A can be degraded by MMP-2 upon its dissociation from SMYD2, suggesting the protective role of SMYD2 in sarcomere stability. Our results uncover SMYD2 glutathionylation as a novel molecular mechanism by which ROS contribute to sarcomere destabilization and muscle dysfunction.

SMYD2 glutathionylation controls sarcomere stability and myofibril integrity

254th National Meeting (2017)

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