Abstract
SUMOylation is a transient posttranslational modification with small-ubiquitin like modifiers (SUMO1, SUMO2 and SUMO3) covalently attached to their target-proteins via a multi-step enzymatic cascade. SUMOylation modifies protein-protein interactions, enzymatic-activity or chromatin binding in a multitude of key cellular processes, acting as a highly dynamic molecular switch. To guarantee the rapid kinetics, SUMO target-proteins are kept in a tightly controlled equilibrium of SUMOylation and deSUMOylation. DeSUMOylation is maintained by the SUMO-specific proteases, predominantly of the SENP family. SENP1 and SENP2 represent family members tuning SUMOylation status of all three SUMO isoforms, while SENP3 and SENP5 are dedicated to detach mainly SUMO2/3 from its substrates. SENP6 and SENP7 cleave polySUMO2/3 chains thereby countering the SUMO-targeted-Ubiquitin-Ligase (StUbL) pathway. Several biochemical studies pinpoint towards the SENPs as critical enzymes to control balanced SUMOylation/deSUMOylation in cardiovascular health and disease. This study aims to review the current knowledge about the SUMO-specific proteases in the heart and provides an integrated view of cardiac functions of the deSUMOylating enzymes under physiological and pathological conditions.
Highlights
Cardiovascular diseases such as atherosclerosis, acute coronary disease, cardiomyopathies and heart failure are leading causes of morbidity and mortality worldwide (Murray and Lopez, 1997)
We propose that SENP6 and SENP7, by counteracting RNF4 action on PML and, possibly other targets might interplay in the complex regulatory landscape of ischemic adaptation
Many aspects of the regulation and function of sentrinspecific protease (SENP) have been analyzed in vitro and in vivo, several open questions remain regarding their specific role in the heart
Summary
Cardiovascular diseases such as atherosclerosis, acute coronary disease, cardiomyopathies and heart failure are leading causes of morbidity and mortality worldwide (Murray and Lopez, 1997). Much progress has been made to identify the underlying molecular mechanisms associated with cardiac diseases, only few new drugs were derived from such efforts within the past years (Kairouz et al, 2012; Münzel et al, 2015; Mendler et al, 2016; Heusch, 2020). There is an urgent need to deeper understand the molecular mechanisms of cardiac pathologies to develop new therapeutic approaches for effective cardioprotection. Small proteins like ubiquitin and ubiquitin-like modifiers (ULM) can become covalently attached to distinct lysine residues of their target proteins regulating several aspects of cellular proteostasis. SUMO (small ubiquitin-related modifier) is a typical ULM (van der Veen and Ploegh, 2012; Flotho and Melchior, 2013) with four different isoforms in mammals (SUMO1-4), where only SUMO1-3 are expressed ubiquitously. SUMO1-3 are synthesized as precursor proteins that undergo carboxy-terminal processing (Müller et al, 2001) to expose a di-glycine (diGly) motif required for conjugation
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