2. Academic Validation
  3. TNIK: A redox sensor in endothelial cell permeability

TNIK: A redox sensor in endothelial cell permeability

  • Sci Adv. 2024 Dec 20;10(51):eadk6583. doi: 10.1126/sciadv.adk6583.
Justin Joachim 1,  Davide Maselli 1,  Emmanouela Petsolari 2,  Jurjan Aman 3,  Pamela Swiatlowska 4,  David Killock 1,  Hiba Chaudhry 1,  Ali A Zarban 1 5,  Mosharraf Sarker 6,  Paul Fraser 1,  Simon J Cleary 7,  Richard Amison 8,  Isabelle Cuthbert 1,  Yue Yang 1,  Magda Meier 9,  Franca Fraternali 2 10 11,  Susan D Brain 1,  Ajay M Shah 1,  Aleksandar Ivetic 1
Affiliations

Affiliations

  • 1 School of Cardiovascular and Metabolic Medicine and Sciences, James Black Centre, BHF Centre of Research Excellence, 125 Coldharbour Lane, King's College London, London SE5 9NU, UK.
  • 2 Randall Centre for Cell and Molecular Biology, King's College London, London SE1 1UL, UK.
  • 3 Department of Pulmonary Medicine, Amsterdam University Medical Center, location VUMC, Amsterdam, The Netherlands.
  • 4 Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, UK.
  • 5 Department of Pharmacological Sciences, Faculty of Pharmacy, Jazan University, Saudi Arabia.
  • 6 Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, Liverpool, UK.
  • 7 Institute of Pharmaceutical Science, King's College London, Floor 5, Southwark Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
  • 8 School of Cancer and Pharmaceutical Sciences, Pulmonary Pharmacology Unit, King's College London, London, UK.
  • 9 School of Genetics and Genomic Medicine, University College London Institute of Child Health, London, UK.
  • 10 Division of Biosciences, Structural and Molecular Biology Department, University College London, Darwin (SMB) Building, Gower Street, London WC1E 6BT, UK.
  • 11 Department of Structural and Molecular Biology, Division of Biosciences and Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK Department of Biological Sciences, Birkbeck, University of London, London WC1E 7HX, United Kingdom.
PMID: 39705357 DOI: 10.1126/sciadv.adk6583
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 H2O2-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.

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