Tnik: A redox sensor in endothelial cell permeability

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

Tnik: A redox sensor in endothelial cell permeability

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

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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 2O 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.

Original language	English
Pages (from-to)	eadk6583
Journal	Science Advances
Volume	10
Issue number	51
DOIs	https://doi.org/10.1126/sciadv.adk6583
Publication status	Published - 20 Dec 2024

Keywords

Humans
Oxidation-Reduction
Endothelial Cells/metabolism
Phosphorylation
Protein Serine-Threonine Kinases/metabolism
Tumor Necrosis Factor-alpha/metabolism
Cell Membrane Permeability
Animals
Cytoskeletal Proteins/metabolism
Hydrogen Peroxide/metabolism
Reactive Oxygen Species/metabolism
Human Umbilical Vein Endothelial Cells/metabolism
Signal Transduction
Membrane Proteins/metabolism
Microfilament Proteins

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/sciadv.adk6583

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Joachim, J., Maselli, D., Petsolari, E., Aman, J., Swiatlowska, P., Killock, D., Chaudhry, H., Zarban, A. A., Sarker, M., Fraser, P., Cleary, S. J., Amison, R., Cuthbert, I., Yang, Y., Meier, M., Fraternali, F., Brain, S. D., Shah, A. M., & Ivetic, A. (2024). Tnik: A redox sensor in endothelial cell permeability. Science Advances, 10(51), eadk6583. https://doi.org/10.1126/sciadv.adk6583

@article{f5b542d747b94f96a0386732d2fd7164,

title = "Tnik: A redox sensor in endothelial cell permeability",

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 2O 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. ",

keywords = "Humans, Oxidation-Reduction, Endothelial Cells/metabolism, Phosphorylation, Protein Serine-Threonine Kinases/metabolism, Tumor Necrosis Factor-alpha/metabolism, Cell Membrane Permeability, Animals, Cytoskeletal Proteins/metabolism, Hydrogen Peroxide/metabolism, Reactive Oxygen Species/metabolism, Human Umbilical Vein Endothelial Cells/metabolism, Signal Transduction, Membrane Proteins/metabolism, Microfilament Proteins",

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

year = "2024",

month = dec,

day = "20",

doi = "10.1126/sciadv.adk6583",

language = "English",

volume = "10",

pages = "eadk6583",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "51",

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Joachim, J , Maselli, D, Petsolari, E, Aman, J, Swiatlowska, P, Killock, D , Chaudhry, H , Zarban, AA, Sarker, M, Fraser, P , Cleary, SJ , Amison, R , Cuthbert, I , Yang, Y, Meier, M, Fraternali, F , Brain, SD , Shah, AM & Ivetic, A 2024, 'Tnik: A redox sensor in endothelial cell permeability', Science Advances, vol. 10, no. 51, pp. eadk6583. https://doi.org/10.1126/sciadv.adk6583

TY - JOUR

T1 - Tnik

T2 - A redox sensor in endothelial cell permeability

AU - Joachim, Justin

AU - Maselli, Davide

AU - Petsolari, Emmanouela

AU - Aman, Jurjan

AU - Swiatlowska, Pamela

AU - Killock, David

AU - Chaudhry, Hiba

AU - Zarban, Ali A

AU - Sarker, Mosharraf

AU - Fraser, Paul

AU - Cleary, Simon J

AU - Amison, Richard

AU - Cuthbert, Isabelle

AU - Yang, Yue

AU - Meier, Magda

AU - Fraternali, Franca

AU - Brain, Susan D

AU - Shah, Ajay M

AU - Ivetic, Aleksandar

PY - 2024/12/20

Y1 - 2024/12/20

N2 - 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 2O 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.

AB - 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 2O 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.

KW - Humans

KW - Oxidation-Reduction

KW - Endothelial Cells/metabolism

KW - Phosphorylation

KW - Protein Serine-Threonine Kinases/metabolism

KW - Tumor Necrosis Factor-alpha/metabolism

KW - Cell Membrane Permeability

KW - Animals

KW - Cytoskeletal Proteins/metabolism

KW - Hydrogen Peroxide/metabolism

KW - Reactive Oxygen Species/metabolism

KW - Human Umbilical Vein Endothelial Cells/metabolism

KW - Signal Transduction

KW - Membrane Proteins/metabolism

KW - Microfilament Proteins

U2 - 10.1126/sciadv.adk6583

DO - 10.1126/sciadv.adk6583

M3 - Article

C2 - 39705357

SN - 2375-2548

VL - 10

SP - eadk6583

JO - Science Advances

JF - Science Advances

IS - 51

ER -

Tnik: A redox sensor in endothelial cell permeability

Abstract

Keywords

UN SDGs

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