Profiling the Murine SUMO Proteome in Response to Cardiac Ischemia and Reperfusion Injury

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.

The Function of SUMOylation and Its Critical Roles in Cardiovascular Diseases and Potential Clinical Implications

“…To identify the potential target proteins of SUMOylation in the mouse heart with cardiac I/R, an unbiased proteomic analysis was conducted. There were 102 proteins that significantly interacted with SUMO1, including the composition of the SUMO mechanism and the ubiquitin proteasome system [ 143 , 144 ], multiple subunits of 20S proteasome core particle, and metabolic enzymes involved in glycolytic and oxidative metabolic pathways [ 145 ]. High molecular weight SUMO1 conjugates were significantly reduced 24 h after reperfusion.…”

“…Further, 55 proteins were found to be potential SUMO2/3 target proteins, including ubiquitin and proteasome subunits, gene expression regulators and transcription factors, RNA binding proteins and splicing regulators, heat shock proteins, and specific proteins that play important roles in cardiac function. Myocardial ischemia decreased the SUMO level of the whole protein and the number and catalytic activity of de-SUMO enzymes [ 145 ]. The heart SUMO2 target protein undergoes a dynamic adaptation process in cardiac I/R.…”

“…Only one protein was SUMOylated differently at ischemia, and 8 and 11 target proteins were significantly altered 1 and 24 h after reperfusion, respectively. SENP3 is the major deSUMOylation enzyme in mouse hearts [ 145 ]. These results identified potential targets of SUMOylation during cardiac I/R and provided potential therapeutic targets for the treatment of cardiac ischemia.…”

SUMOylation as a Therapeutic Target for Myocardial Infarction

“…Another study showed that the dynamics of the SUMOylation/deSUMOylation was altered during MI/R injury correlating with the decrease in SENPs activities, especially that of SENP3 ( 54 ). Presumably, the SUMOylation system may control the response of the heart to hypoxic/ischemic stress ( 55 ). Nevertheless, little is known about the regulation of the SUMOylation system and the potential target proteins during MI.…”

Plasma Exosome-Derived SENP1 May Be a Potential Prognostic Predictor for Melanoma

“…Human desumoylation proteases SENPs, including SENP1, SENP 2, SENP 3, SENP 5, SENP 6 and SENP 7, play a key role in this pathway ( 19 ). One is to catalyze the transformation of SUMO precursor into its active form; the other is to cut off the isopeptide bond between SUMO and the target protein to realize desumoylation ( 20 ). SENP is involved in the regulation of the cell cycle, cell proliferation, oxidative stress signaling or tumor gene fusion, leading to tumor formation.…”