MALT1 Protease Activation Triggers Acute Disruption of Endothelial Barrier Integrity via CYLD Cleavage.
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.
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Linda R
LR
Klei
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Dong
D
Hu
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Robert
R
Panek
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Danielle N
DN
Alfano
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Rachel E
RE
Bridwell
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Kelly M
KM
Bailey
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Katherine I
KI
Oravecz-Wilson
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Vincent J
VJ
Concel
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Emily M
EM
Hess
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Matthew
M
Van Beek
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Phillip C
PC
Delekta
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Shufang
S
Gu
Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Simon C
SC
Watkins
Immunology Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Adrian T
AT
Ting
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19406, USA.
Peter J
PJ
Gough
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19406, USA.
Kevin P
KP
Foley
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19406, USA.
John
J
Bertin
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: linda.mcallister@chp.edu.
Linda M
LM
McAllister-Lucas
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: lucaspc@upmc.edu.
Peter C
PC
Lucas
D000818:Animals; D001692:Biological Transport; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology*; D000074749:Deubiquitinating Enzyme CYLD; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000187:drug effects* / Q000648:ultrastructure; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D010539:Permeability / Q000187:drug effects; D061251:Primary Cell Culture; D044463:Receptor, PAR-1 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*
D053468:CARD Signaling Adaptor Proteins; C498975:Card10 protein, mouse; D016328:NF-kappa B; D009363:Neoplasm Proteins; D044463:Receptor, PAR-1; D051550:I-kappa B Kinase; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D013917:Thrombin; D020169:Caspases; D003546:Cysteine Endopeptidases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
Bcl10; CARD10; CARMA3; CYLD; G protein-coupled receptor (GPCR); MALT1 protease; NF-κB; Protease activated receptor-1 (PAR1); endothelial permeability; thrombin
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