SUMO proteins in the cardiovascular system: friend or foe?

Abstract

Post-translational modifications (PTMs) are crucial for the adaptation of various signalling pathways to ensure cellular homeostasis and proper adaptation to stress. PTM is a covalent addition of a small chemical functional group such as a phosphate group (phosphorylation), methyl group (methylation), or acetyl group (acetylation); lipids like hydrophobic isoprene polymers (isoprenylation); sugars such as a glycosyl group (glycosylation); or even small peptides such as ubiquitin (ubiquitination), SUMO (SUMOylation), NEDD8 (neddylation), etc. SUMO modification changes the function and/or fate of the protein especially under stress conditions, and the consequences of this conjugation can be appreciated from development to diverse disease processes. The impact of SUMOylation in disease has not been monotonous, rather SUMO is found playing a role on both sides of the coin either facilitating or impeding disease progression. Several recent studies have implicated SUMO proteins as key regulators in various cardiovascular disorders. The focus of this review is thus to summarize the current knowledge on the role of the SUMO family in the pathophysiology of cardiovascular diseases.

SUMOylation as a Therapeutic Target for Myocardial Infarction

“…Different SENP members act on specific SUMOylated proteins ( 31 ). SENP1 and SENP2 catalyze the deSUMOylation of all types of SUMO proteins ( 32 ), whereas SENP3, 5, 6, and 7 prefer SUMO2/3-derived SUMOylated proteins ( 33 , 34 ). Ultimately, deSUMOylation eliminates the effects of SUMOylation on protein functions ( 35 ).…”

“…Although most of the SUMO proteins are present in the nucleus, SUMOylation also occurs on extra-nuclear proteins ( 42 ). Consequently, SUMOylation regulates protein functions in intro-cellular trafficking, apoptosis, protein stability, and enzyme activity ( 9 , 33 ). SUMOylation and deSUMOylation coordinately affect the protein levels and thereby control the extent of MI/R injury ( 30 ).…”

“…Mdivi-1, a pharmacological inhibitor of Drp1, significantly attenuated the mitochondrial abnormality and cardiac injury in the model of overexpressing SENP3 via inhibiting Drp1 after MI/R injury ( 54 ). Moreover, the effort is made to evaluate the Drp1 inhibitor for preventing atherosclerosis in a clinical trial [ ClinicalTrials.gov Identifier: NCT03980548] ( 33 ). TAK-981 inhibits the transfer of SUMO protein from E1 to E2 by binding to the C-terminal of SUMO proteins ( 144 ).…”

SUMO-specific Isopeptidases Tuning Cardiac SUMOylation in Health and Disease

“…Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway, potentially providing a theoretical basis for exiting new therapeutic approaches in cardiac repair after myocardial ischemia. Moreover, since SENP2 plays a significant role in the pathomechanism of atherosclerosis by regulating disturbed-flow induced SUMOylation of ERK5 and p53 leading to endothelial dysfunction, SENP2 might serve as potential target combating atherosclerosis as well (Heo et al, 2013;Heo et al, 2015;Heo et al, 2016;Shetty et al, 2020).…”

Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining

“…Posttranslational modification (PTM) with SUMO (small ubiquitin-like modifier) is key to regulating a gamut of cellular signalling pathways, including transcription, chromatin organisation, nuclear trafficking, DNA replication and DNA repair [1][2][3][4][5] . It is therefore not surprising that deregulation of the SUMO system is associated with a range of prevalent human diseases including neurodegenerative disorders, cardiovascular diseases and cancer [6][7][8] . In humans, several SUMO paralogues exist, with SUMO1-3 being ubiquitously expressed and established as posttranslational modifiers.…”