MALT1 Protease Activation Triggers Acute Disruption of Endothelial Barrier Integrity via CYLD Cleavage

Cell Reports

Simon C. Watkins¹  Matthew Van Beek²  Katherine I. Oravecz-Wilson²  Phillip C. Delekta²  Robert Panek²  Shufang Gu²  Kelly M. Bailey³  Dong Hu⁴  Linda M. McAllister-Lucas⁴  Peter C. Lucas⁴  Vincent J. Concel⁴  Linda R. Klei⁴  Danielle N. Alfano⁴  Rachel E. Bridwell⁴  Emily M. Hess⁴  Adrian T. Ting⁵  Peter J. Gough⁶  Kevin P. Foley⁶  John Bertin⁶ 

[1] Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA;Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA;Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA;Immunology Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19406, USA;

关键词: NF-κB;    thrombin;    Protease activated receptor-1 (PAR1);    CARMA3;    CARD10;    Bcl10;    G protein-coupled receptor (GPCR);    endothelial permeability;    MALT1 protease;    CYLD;   

DOI  :  10.1016/j.celrep.2016.08.080

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown