P66Shc Mediates SUMO2-induced Endothelial Dysfunction

Jitendra Kumar; Shravan Uppulapu; Sujata Kumari; Kanika Sharma; William Paradee; Ravi Yadav; Vikas Kumar; Santosh Kumar

doi:10.1101/2024.01.24.577109

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P66Shc Mediates SUMO2-induced Endothelial Dysfunction

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Open access

P66Shc Mediates SUMO2-induced Endothelial Dysfunction

Jitendra Kumar, Shravan Uppulapu, Sujata Kumari, Kanika Sharma, William Paradee, Ravi Yadav, Vikas Kumar and Santosh Kumar

bioRxiv

Cold Spring Harbor Laboratory Press

01/26/2024

DOI: 10.1101/2024.01.24.577109

PMCID: PMC10849724

PMID: 38328241

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https://doi.org/10.1101/2024.01.24.577109View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Sumoylation is a post-translational modification that can regulate different physiological functions. Increased sumoylation, specifically conjugation of SUMO2/3 (small ubiquitin like modifier 2/3), is detrimental to vascular health. However, the molecular mechanism mediating this effect is poorly understood. Here, we demonstrate that SUMO2 modifies p66Shc, which impairs endothelial function. In endothelial cells, knockdown of p66Shc blunted SUMO2-induced increases in reactive oxygen species and inflammation. Using multiple approaches, we show that p66Shc is a direct target of SUMO2. Mass spectrometry identified that SUMO2 modified lysine-81 in the unique collagen homology-2 domain of p66Shc. SUMO2ylation of p66Shc increased phosphorylation at serine-36 (S36), causing it to translocate to the mitochondria, which are key steps regulating the oxidative function of p66Shc. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. Ingenuity pathway analysis showed that SUMO2ylation of p66ShcK81 regulated multiple pathways in endothelial cells, including Rac1-GTPase. Finally, to examine the physiological significance of this posttranslational modification in vivo, we generated p66ShcK81R knockin mice. Unlike wild-type mice, the aortic rings of p66ShcK81R knockin mice were resistant to SUMO2-induced endothelial dysfunction. Collectively, our work uncovers a posttranslational modification of redox protein p66Shc and identifies SUMO2-p66Shc signaling as a regulator of vascular endothelial function.Competing Interest StatementThe authors have declared no competing interest.

Phosphorylation

Physiology

Aorta

Endothelial cells

Homology

Mass spectroscopy

Molecular modelling

Post-translation

Rac1 protein

Reactive oxygen species

SUMO protein

Ubiquitin

Details

Title: Subtitle: P66Shc Mediates SUMO2-induced Endothelial Dysfunction
Creators: Jitendra Kumar - University of Iowa
Shravan Uppulapu - University of Iowa
Sujata Kumari - University of Iowa
Kanika Sharma - University of Nebraska Medical Center
William Paradee - University of Iowa
Ravi Yadav
Vikas Kumar - University of Nebraska Medical Center
Santosh Kumar - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2024.01.24.577109
PMID: 38328241
PMCID: PMC10849724
Publisher: Cold Spring Harbor Laboratory Press; Cold Spring Harbor
Language: English
Date posted: 01/26/2024
Academic Unit: Cardiovascular Medicine; Medicine Administration; Internal Medicine
Record Identifier: 9984557843502771

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