Abstract
SUMOylation is a reversible posttranslational modification pathway catalyzing the conjugation of small ubiquitin-related modifier (SUMO) proteins to lysine residues of distinct target proteins. SUMOylation modifies a wide variety of cellular regulators thereby affecting a multitude of key processes in a highly dynamic manner. The SUMOylation pathway displays a hallmark in cellular stress-adaption, such as heat or redox stress. It has been proposed that enhanced cellular SUMOylation protects the brain during ischemia, however, little is known about the specific regulation of the SUMO system and the potential target proteins during cardiac ischemia and reperfusion injury (I/R). By applying left anterior descending (LAD) coronary artery ligation and reperfusion in mice, we detect dynamic changes in the overall cellular SUMOylation pattern correlating with decreased SUMO deconjugase activity during I/R injury. Further, unbiased system-wide quantitative SUMO-proteomics identified a sub-group of SUMO targets exhibiting significant alterations in response to cardiac I/R. Notably, transcription factors that control hypoxia- and angiogenesis-related gene expression programs, exhibit altered SUMOylation during ischemic stress adaptation. Moreover, several components of the ubiquitin proteasome system undergo dynamic changes in SUMO conjugation during cardiac I/R suggesting an involvement of SUMO signaling in protein quality control and proteostasis in the ischemic heart. Altogether, our study reveals regulated candidate SUMO target proteins in the mouse heart, which might be important in coping with hypoxic/proteotoxic stress during cardiac I/R injury.
Highlights
Acute coronary occlusion is a leading cause of morbidity and mortality in western countries according to the world health organization [1]
Proteins were separated by SDS-PAGE and the small ubiquitin-related modifier (SUMO) pattern was analyzed by anti-SUMO immunoblotting (Figure 1A,B and Figure S1B,C)
The most prominent SUMO1 target protein RanGAP1 showed slightly increased SUMOylation after reperfusion (Figure 1A), high molecular weight (HMW) SUMO1 conjugates altogether exhibit a significant decrease after 24 h reperfusion (Figure 1A and Figure S1B)
Summary
Acute coronary occlusion is a leading cause of morbidity and mortality in western countries according to the world health organization [1]. The important role of the SUMO system in cardiac development and the pathomechanism of heart failure has been demonstrated by cardiac specific genetic modulation of the SUMO machinery (i.e., SUMOs, conjugation enzymes and SENPs) [7], but the role of SUMOylation in cardiac I/R injury has remained largely elusive [16,17,18,19,20]. Whereas previous studies concentrated mainly on the altered pattern of SUMOylation of individual proteins in the heart, the SUMO conjugation/deconjugation machinery coordinates signaling networks by targeting groups of protein functioning in common signaling pathways. We provide evidence that the general SUMOylation pattern of proteins is dynamically regulated in the heart with decreased SENP activities throughout ischemia and reperfusion. We identify several SUMO1 and SUMO2 target proteins in vivo, with a sub-group of proteins showing a regulated pattern during I/R injury, e.g., hypoxia- or angiogenesis related transcription factors and proteasome subunits which might be important in coping with hypoxic and proteotoxic stress during cardiac I/R damage
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