MALT1 has both protease activity-dependent and -independent roles in innate and adaptive immunity (IRM10P.739)

Abstract Hetero-trimeric CARMA/BCL10/MALT1 CBM complexes play important roles in B and T cell antigen receptor signaling and other pathways. Previous studies have suggested that MALT1 functions as both a scaffolding protein to activate NF-κB through recruitment of ubiquitin ligases, and as a cysteine protease to cleave and inactivate downstream signaling molecules such as A20 and CYLD. However, little is known about the relative importance of these two distinct activities in orchestrating immune responses. Utilizing mice homozygous for either null or protease-dead C461A mutations in MALT1, we found that some but not all MALT1 functions were dependent upon its protease activity. Although protease-dead mice had normal follicular B cell and T cell populations in the spleen, defects were observed in the generation of splenic marginal zone and peritoneal B1 B cells. Ex vivo, B cell receptor-stimulated proliferation was normal, but CD4+ and CD8+ T cells displayed decreased activation-induced proliferation and IL-2 production. C-type lectin receptor stimulation of cytokine production by dendritic cells was also found to be partially dependent upon protease activity. In vivo, protease-dead mice displayed severely reduced basal immunoglobulin levels, and defective T-dependent and T-independent immune responses. Our findings suggest that pharmacologic inhibition of MALT1 protease activity may be a useful therapeutic approach for diseases linked to uncontrolled immune cell activation.