SMYD2 glutathionylation contributes to degradation of sarcomeric proteins

Dhanushka N. P. Munkanatta Godage, Garrett C. VanHecke, Kusal T. G. Samarasinghe, Han-Zhong Feng, Mark Hiske, Joshua Holcomb, Zhe Yang, Jian-Ping Jin, Charles S. Chung and Young-Hoon Ahn ()
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Dhanushka N. P. Munkanatta Godage: Wayne State University
Garrett C. VanHecke: Wayne State University
Kusal T. G. Samarasinghe: Wayne State University
Han-Zhong Feng: Wayne State University School of Medicine
Mark Hiske: Wayne State University School of Medicine
Joshua Holcomb: Wayne State University School of Medicine
Zhe Yang: Wayne State University School of Medicine
Jian-Ping Jin: Wayne State University School of Medicine
Charles S. Chung: Wayne State University School of Medicine
Young-Hoon Ahn: Wayne State University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Reactive oxygen species (ROS) contribute to the etiology of multiple muscle-related diseases. There is emerging evidence that cellular stress can lead to destabilization of sarcomeres, the contractile unit of muscle. However, it is incompletely understood how cellular stress induces structural destabilization of sarcomeres. Here we report that glutathionylation of SMYD2 contributes to a loss of myofibril integrity and degradation of sarcomeric proteins mediated by MMP-2 and calpain 1. We used a clickable glutathione approach in a cardiomyocyte cell line and found selective glutathionylation of SMYD2 at Cys13. Biochemical analysis demonstrated that SMYD2 upon oxidation or glutathionylation at Cys13 loses its interaction with Hsp90 and N2A, a domain of titin. Upon dissociation from SMYD2, N2A or titin is degraded by activated MMP-2, suggesting a protective role of SMYD2 in sarcomere stability. Taken together, our results support that SMYD2 glutathionylation is a novel molecular mechanism by which ROS contribute to sarcomere destabilization.

Date: 2018
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DOI: 10.1038/s41467-018-06786-x

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