Abstract
Abstract 214: Sumo2 Regulates Oxidative Function Of Adaptor Protein P66shc
Arteriosclerosis, thrombosis, and vascular biology, Vol.43(Suppl_1)
05/2023
DOI: 10.1161/atvb.43.suppl_1.214
Abstract
Abstract only SUMOylation is a highly dynamic post-translational modification which regulates protein function and/or stability. It involves conjugation of SUMOs ( S mall U biquitin-Like Mo difier s ) to the lysine residue/s of target proteins mediated via a highly coordinated enzymatic mechanism. Studies have shown that promoting SUMOylation (SUMO2/3) causes vascular endothelial dysfunction and accelerates atherosclerosis. We reported that SUMO2 overexpression in endothelial cells promotes oxidative stress and impairs endothelial function. However, the mechanism is not well understood. Adaptor protein p66Shc is a master regulator of oxidative stress and endothelial function. Genetic deletion of p66Shc protects mice against endothelial dysfunction due to metabolic dysregulation. Prior studies have shown that lysine modification of p66Shc regulates its oxidative function. As SUMOylation primarily occurs on lysine residue, we examined if p66Shc is a target of SUMO2. In this study, we show that p66Shc is a direct target of SUMO2. Using endothelial cells and HEK-293 cells, we show that overexpression of SUMO2 leads to p66Shc SUMO2ylation which is further increased in presence of E2-ligase Ubc9 and reduced by deSUMOylating enzyme SENP1. SUMO2ylation of p66Shc increases oxidative activation (serine-36 phosphorylation) of p66Shc which is essential for reactive oxygen production by p66Shc. Using mass spectroscopic study, we identified that lysine-81 is the only lysine present in CH2 domain which is getting SUMO2ylated. Rendering p66ShcK81 non-sumoylatable (p66ShcK81R) prevented the SUMO2ylation of p66Shc. In endothelial cells, overexpression of p66ShcK81R prevented the SUMO2-induced increase in serine-36 phosphorylation and mitochondrial translocation of p66Shc, which are essential for oxidative function of p66Shc. Collectively, we present a novel molecular mechanism via which SUMO2 regulates the oxidative function of p66Shc and identify a unique post-translational regulation of p66Shc in endothelial cells.
Details
- Title: Subtitle
- Abstract 214: Sumo2 Regulates Oxidative Function Of Adaptor Protein P66shc
- Creators
- Jitendra Kumar - University of IowaShravan kumar Uppulapu - University of Iowasujata kumari - University of IowaKanika Sharma - Univ of Nebraska, Omaha, NEVikas Kumar - University of Nebraska at OmahaSantosh Kumar - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.43(Suppl_1)
- DOI
- 10.1161/atvb.43.suppl_1.214
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2023
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984473951502771
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