{"doi":"10.1101/2024.01.24.577109","title":"p66Shc Mediates SUMO2-induced Endothelial Dysfunction","abstract":"Background: 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. Methods: mice to induce hyperlipidemia. Next, to determine p66ShcK81-SUMO2ylation-induced changes in endothelial cell signaling, we performed mass spectrometry followed by Ingenuity Pathway Analysis. Results: Our data reveal that p66Shc mediates the effects of SUMO2 on endothelial cells. 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, a step critical for oxidative function of p66Shc. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. P66ShcK81R knockin mice were resistant to endothelial dysfunction induced by SUMO2ylation and hyperlipidemia. Ingenuity Pathway Analysis revealed multiple signaling pathways regulated by p66ShcK81-SUMO2ylation in endothelial cells, highlighting Rho-GTPase as a major pathway affected by SUMO2-p66ShcK81. Conclusions: Collectively, our work reveals SUMO2-p66Shc signaling as a fundamental regulator of vascular endothelial function. We discovered that p66ShcK81 is an upstream modification regulating p66Shc signaling and mediates hyperlipidemia-induced endothelial dysfunction and oxidative stress.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":487794,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":736241,"name":"Shravan Kumar Uppulapu","orcid":"0000-0001-5591-8167","position":1,"is_corresponding":false},{"id":1332049,"name":"Sujata Kumari","orcid":"0000-0002-6374-8417","position":2,"is_corresponding":false},{"id":1332050,"name":"Kanika Sharma","orcid":"0000-0001-7847-4319","position":3,"is_corresponding":false},{"id":768599,"name":"William Paradee","orcid":null,"position":4,"is_corresponding":false},{"id":519098,"name":"Ravi Prakash Yadav","orcid":"0000-0002-6243-8388","position":5,"is_corresponding":false},{"id":320558,"name":"Vikas Kumar","orcid":"0000-0001-7513-6832","position":6,"is_corresponding":false},{"id":618406,"name":"Santosh Kumar","orcid":"0000-0003-1418-2020","position":7,"is_corresponding":false},{"id":740943,"name":"Jitendra Kumar","orcid":"0000-0003-4222-446X","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:08:10.215754Z","pmid":"38328241","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}