TNIK: A redox sensor in endothelial cell permeability

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2024-12-20 DOI:10.1126/sciadv.adk6583

Justin Joachim, Davide Maselli, Emmanouela Petsolari, Jurjan Aman, Pamela Swiatlowska, David Killock, Hiba Chaudhry, Ali A. Zarban, Mosharraf Sarker, Paul Fraser, Simon J. Cleary, Richard Amison, Isabelle Cuthbert, Yue Yang, Magda Meier, Franca Fraternali, Susan D. Brain, Ajay M. Shah, Aleksandar Ivetic

{"title":"TNIK: A redox sensor in endothelial cell permeability","authors":"Justin Joachim, Davide Maselli, Emmanouela Petsolari, Jurjan Aman, Pamela Swiatlowska, David Killock, Hiba Chaudhry, Ali A. Zarban, Mosharraf Sarker, Paul Fraser, Simon J. Cleary, Richard Amison, Isabelle Cuthbert, Yue Yang, Magda Meier, Franca Fraternali, Susan D. Brain, Ajay M. Shah, Aleksandar Ivetic","doi":"10.1126/sciadv.adk6583","DOIUrl":null,"url":null,"abstract":"Dysregulation of endothelial barrier integrity can lead to vascular leak and potentially fatal oedema. TNF-α controls endothelial permeability during inflammation and requires the actin organizing Ezrin-Radixin-Moesin (ERM) proteins. We identified TRAF2 and NCK-interacting kinase (TNIK) as a kinase directly phosphorylating and activating ERM, specifically at the plasma membrane of primary human endothelial cells. TNIK mediates TNF-α–dependent cellular stiffness and paracellular gap formation in vitro and is essential in driving inflammatory oedema formation in vivo. Unlike its homologs, TNIK activity is negatively and reversibly regulated by H 2 O 2 -mediated oxidation of C202 within the kinase domain. TNIK oxidation results in intermolecular disulfide bond formation and loss of kinase activity. Pharmacologic inhibition of endogenous reactive oxygen species production in endothelial cells elevated TNIK-dependent ERM phosphorylation, endothelial cell contraction, and cell rounding. Together, we highlight an interplay between TNIK, ERM phosphorylation, and redox signalling in regulating TNF-induced endothelial cell permeability.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"90 1","pages":""},"PeriodicalIF":11.7000,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1126/sciadv.adk6583","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Dysregulation of endothelial barrier integrity can lead to vascular leak and potentially fatal oedema. TNF-α controls endothelial permeability during inflammation and requires the actin organizing Ezrin-Radixin-Moesin (ERM) proteins. We identified TRAF2 and NCK-interacting kinase (TNIK) as a kinase directly phosphorylating and activating ERM, specifically at the plasma membrane of primary human endothelial cells. TNIK mediates TNF-α–dependent cellular stiffness and paracellular gap formation in vitro and is essential in driving inflammatory oedema formation in vivo. Unlike its homologs, TNIK activity is negatively and reversibly regulated by H 2 O 2 -mediated oxidation of C202 within the kinase domain. TNIK oxidation results in intermolecular disulfide bond formation and loss of kinase activity. Pharmacologic inhibition of endogenous reactive oxygen species production in endothelial cells elevated TNIK-dependent ERM phosphorylation, endothelial cell contraction, and cell rounding. Together, we highlight an interplay between TNIK, ERM phosphorylation, and redox signalling in regulating TNF-induced endothelial cell permeability.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.