@article{46a0dcc9156942ef9790f80e6ab39a91,
title = "MALT1 Protease Activation Triggers Acute Disruption of Endothelial Barrier Integrity via CYLD Cleavage",
abstract = "Microvascular endothelial cells maintain a tight barrier to prevent passage of plasma and circulating immune cells into the extravascular tissue compartment, yet endothelial cells respond rapidly to vasoactive substances, including thrombin, allowing transient paracellular permeability. This response is a cornerstone of acute inflammation, but the mechanisms responsible are still incompletely understood. Here, we demonstrate that thrombin triggers MALT1 to proteolytically cleave cylindromatosis (CYLD). Fragmentation of CYLD results in microtubule disruption and a cascade of events leading to endothelial cell retraction and an acute permeability response. This finding reveals an unexpected role for the MALT1 protease, which previously has been viewed mostly as a driver of pro-inflammatory NF-κB signaling in lymphocytes. Thus, MALT1 not only promotes immune cell activation but also acutely regulates endothelial cell biology, actions that together facilitate tissue inflammation. Pharmacologic inhibition of MALT1 may therefore have synergistic impact by targeting multiple disparate steps in the overall inflammatory response.",
keywords = "Bcl10, CARD10, CARMA3, CYLD, G protein-coupled receptor (GPCR), MALT1 protease, NF-κB, Protease activated receptor-1 (PAR1), endothelial permeability, thrombin",
author = "Klei, {Linda R.} and Dong Hu and Robert Panek and Alfano, {Danielle N.} and Bridwell, {Rachel E.} and Bailey, {Kelly M.} and Oravecz-Wilson, {Katherine I.} and Concel, {Vincent J.} and Hess, {Emily M.} and {Van Beek}, Matthew and Delekta, {Phillip C.} and Shufang Gu and Watkins, {Simon C.} and Ting, {Adrian T.} and Gough, {Peter J.} and Foley, {Kevin P.} and John Bertin and McAllister-Lucas, {Linda M.} and Lucas, {Peter C.}",
note = "Funding Information: This work was supported by NIH/NHLBI grant R01-HL082914. Resources for microscopic imaging were provided by the University of Pittsburgh Center for Biologic Imaging. The authors wish to thank all members of the Lucas/McAllister lab for their insights and support. We also thank David Antonetti (University of Michigan) for guidance and use of ECIS equipment during the early phase of this project, Yulia Komarova (University of Illinois College of Medicine, Chicago) for advice on microtubule imaging and quantification, and Cora-Jean Edgell (University of North Carolina) for the gift of EA.hy926 cells. At the time of original submission, P.J.G., K.P.F., and J.B. were employees and shareholders of GlaxoSmithKline. Publisher Copyright: {\textcopyright} 2016 The Authors",
year = "2016",
month = sep,
day = "27",
doi = "10.1016/j.celrep.2016.08.080",
language = "English",
volume = "17",
pages = "221--232",
journal = "Cell Reports",
issn = "2211-1247",
number = "1",
}