P66Shc Mediates SUMO2-induced Endothelial Dysfunction.
Jitendra KumarShravan K UppulapuSujata KumariKanika SharmaWilliam ParadeeRavi Prakash YadavVikas KumarSantosh KumarPublished in: bioRxiv : the preprint server for biology (2024)
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. 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, causing it to translocate to the mitochondria. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. Ingenuity pathway analysis showed that majority of effects of p66Shc SUMO2ylation were mediated via p66ShcK81. Finally, 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.
Keyphrases
- mass spectrometry
- healthcare
- diabetic rats
- high glucose
- drug induced
- oxidative stress
- cell death
- skeletal muscle
- small molecule
- metabolic syndrome
- genome wide
- gene expression
- protein kinase
- liquid chromatography
- ms ms
- endoplasmic reticulum
- amino acid
- insulin resistance
- gas chromatography
- tandem mass spectrometry
- human health