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

Abstract

SUMMARY 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.

Malt1 Protease Deficiency in Mice Disrupts Immune Homeostasis at Environmental Barriers and Drives Systemic T Cell–Mediated Autoimmunity

“…One such case is loss of function mutations in MALT1, which cause IPEXlike autoimmune manifestations in humans and are fatal unless treated with hematopoietic stem cell transplantation (10)(11)(12)(13)(14). The MALT1 paracaspase is a ubiquitously expressed key regulator of canonical NF-kB activation downstream of multiple receptors such as the TCR, BCR, FcgRs, several C-type lectin receptors, or G protein-coupled receptors (15)(16)(17)(18)(19). Together with BCL10 and various CARD molecules and upon activation, MALT1 forms the "CBM" signalosome (20), which acts as a scaffold for recruitment of effector proteins that ultimately trigger NF-kB-dependent signaling (21)(22)(23).…”

GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein

“…Together, our findings that GRK2 dissociates from MALT1 in response to AgR stimulation and that GRK2 binds to the MALT1 including its binding partner BCL10 and the deubiquitinases A20 and cylindromatosis (CYLD) (15)(16)(17)(18)(19). Collectively, these cleavage events not only optimize NF-κB activation but also regulate cellular adhesion and enhance the related c-Jun N-terminal kinase (JNK) signaling pathway (20).…”

The LUBAC participates in Lysophosphatidic Acid-induced NF-κB Activation

“…This enzymatic activity is crucial for the development of regulatory T cells, the differentiation of Th17 lymphocytes, and governs Tcell receptor (TCR)-driven proliferation and IL-2 production [9][10][11]13]. Interestingly, MALT1 protease activity was also found to modulate the integrity of the epithelial barrier in response to thrombin [3], therefore suggesting that MALT1 could be unleashed following GPCRs engagement.…”