MALT1 proteolytic activity is necessary for FcɛRI-mediated cytokine production in mast cells

Abstract

Abstract IgE mediated mast cell activation triggered by multivalent antigen crosslinking of FcɛRI receptors leads to the release of a wide range of inflammatory mediators. Recent studies revealed that B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (MALT1) are required for IgE-induced nuclear factor κB (NF-κB)-induced proinflammatory cytokine production, while dispensible for mast cell degranulation and leukotriene synthesis. MALT1, a cytoplasmic signaling protein, possesses at least two functions: scaffolding activity and proteolytic activity. The contribution of MALT1 proteolytic activity to mast cell function has not yet been evaluated. We hypothesize that MALT1 proteolytic activity is necessary for FcɛRI-dependent proinflammatory cytokine production. In order to test our hypothesis, we compared the activation of bone marrow derived mast cells (BMMC) from wild type mice, MALT1 knockout mice (MALT1−/−), and mice harboring a mutant, proteolytically inactive MALT1 (MALT1PD/PD). We find MALT1 protease is active in wild-type BMMCs as evidenced by RelB cleavage, and is absent, as expected, in MALT1−/− and MALT1PD/PD BMMCs. Cytokine gene expression and production in response to IgE mediated FcɛRI crosslinking is equivalently abrogated in both MALT1−/− and MALT1PD/PD BMMCs as compared to wild type. These findings suggest that the contribution of MALT1 to IgE mediated responses can be largely attributed to its protease activity. The MALT1 protease has been shown to be drugable, and pharmaceutically targeting the MALT1 protease activity may represent a promising approach to abrogating late phase pathologic mast cell activation.