TNIK: A redox sensor in endothelial cell permeability
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<sub>2</sub>O<sub>2</sub>-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.
Authors
- Magda Meier (ORCID: https://orcid.org/0000-0001-9642-5019)
- Pamela Swiatlowska (ORCID: https://orcid.org/0000-0002-3705-7495)
- David Killock (ORCID: https://orcid.org/0000-0002-3267-8284)
- Simon J. Cleary (ORCID: https://orcid.org/0000-0001-5573-6363)
- Mosharraf H. Sarker (ORCID: https://orcid.org/0000-0003-4698-2161)
- Hiba Chaudhry (ORCID: https://orcid.org/0000-0002-8549-215X)
- Jurjan Aman (ORCID: https://orcid.org/0000-0001-6211-1791)
- Davide Maselli (ORCID: https://orcid.org/0000-0002-2193-1678)
- Franca Fraternali (ORCID: https://orcid.org/0000-0002-3143-6574)
- Justin Joachim (ORCID: https://orcid.org/0000-0002-3748-6900)
- Emmanouela Petsolari
- Aleksandar Ívetic (ORCID: https://orcid.org/0000-0001-9844-6518)
- Susan D. Brain (ORCID: https://orcid.org/0000-0002-9684-8342)
- Ajay M. Shah (ORCID: https://orcid.org/0000-0002-6547-0631)
- Ali A. Zarban (ORCID: https://orcid.org/0000-0003-0328-5032)
- Richard T. Amison (ORCID: https://orcid.org/0000-0002-6616-4599)
- Yue Yang (ORCID: https://orcid.org/0000-0003-3116-3091)
- Paul Fraser (ORCID: https://orcid.org/0000-0001-6345-2061)
- Isabelle Cuthbert
Institutions
- Guy's Hospital (GB)
- King's College London (GB)
- Hammersmith Hospital (GB)
- London Cancer (GB)
- Lung Institute (US)
- Institute of Child Health (IN)
- Amsterdam University Medical Centers (NL)
- King's College Hospital (GB)
- Institute of Structural and Molecular Biology (GB)
- University College London (GB)
- Liverpool John Moores University (GB)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Jazan University (SA)
Publication Details
- Journal
- Science Advances
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1126/sciadv.adk6583
- Citations
- 5
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 1.63