TNIK: A redox sensor in endothelial cell permeability

Joachim, J, Maselli, D, Petsolari, E, Aman, J, Swiatlowska, P, Killock, D, Chaudhry, H, Zarban, AA, Sarker, M ORCID: 0000-0003-4698-2161, Fraser, P, Cleary, SJ, Amison, R, Cuthbert, I, Yang, Y, Meier, M, Fraternali, F, Brain, SD, Shah, AM and Ivetic, A (2024) TNIK: A redox sensor in endothelial cell permeability. Science Advances, 10 (51). pp. 1-19. ISSN 2375-2548

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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<inf>2</inf>O<inf>2</inf>-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.

Item Type:	Article
Uncontrolled Keywords:	Endothelial Cells; Animals; Humans; Hydrogen Peroxide; Reactive Oxygen Species; Microfilament Proteins; Tumor Necrosis Factor-alpha; Cytoskeletal Proteins; Membrane Proteins; Signal Transduction; Cell Membrane Permeability; Oxidation-Reduction; Phosphorylation; Human Umbilical Vein Endothelial Cells; Protein Serine-Threonine Kinases; Ezrin; Humans; Oxidation-Reduction; Endothelial Cells; Phosphorylation; Protein Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Cell Membrane Permeability; Animals; Cytoskeletal Proteins; Hydrogen Peroxide; Reactive Oxygen Species; Human Umbilical Vein Endothelial Cells; Signal Transduction; Membrane Proteins; Microfilament Proteins; Ezrin; 3101 Biochemistry and Cell Biology; 3208 Medical Physiology; 32 Biomedical and Clinical Sciences; 31 Biological Sciences; 2.1 Biological and endogenous factors; 1.1 Normal biological development and functioning; Inflammatory and immune system; Cardiovascular; Humans; Oxidation-Reduction; Endothelial Cells; Phosphorylation; Protein Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Cell Membrane Permeability; Animals; Cytoskeletal Proteins; Hydrogen Peroxide; Reactive Oxygen Species; Human Umbilical Vein Endothelial Cells; Signal Transduction; Membrane Proteins; Microfilament Proteins; Ezrin
Subjects:	R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	American Association for the Advancement of Science (AAAS)
Date of acceptance:	1 September 2023
Date of first compliant Open Access:	10 September 2026
Date Deposited:	10 Sep 2026 14:40
Last Modified:	10 Sep 2026 14:40
DOI or ID number:	10.1126/sciadv.adk6583
URI:	https://researchonline.ljmu.ac.uk/id/eprint/29385

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