Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis

Background: the paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (malt1) is crucial for lymphocyte activation through signaling to the transcription factor nf-κb. besides functioning as a scaffold signaling protein,malt1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific t cell receptor-induced gene expression. recently,small molecule inhibitors of malt1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of b cell lymphoma. however,information on the therapeutic potential of small compound inhibitors that target malt1 protease activity in autoimmunity is still lacking.methods: the present study aimed to elucidate whether malt1 protease inhibitors are also useful in the treatment of lymphocyte-mediated autoimmune pathologies such as multiple sclerosis (ms). for this,we studied the therapeutic potential of a recently identified inhibitor of malt1 protease activity,the phenothiazine derivative mepazine,in the context of experimental autoimmune encephalomyelitis (eae),the main animal model for ms.results: we demonstrate that administration of mepazine prophylactically or after disease onset,can attenuate eae. importantly,while complete absence of malt1 affects the differentiation of regulatory t (treg) cells in vivo,the malt1 protease inhibitor mepazine did not affect treg development.conclusions: altogether,these data indicate that small molecule inhibitors of malt1 not only hold great promise for the treatment of b cell lymphomas but also for autoimmune disorders such as ms. © 2014 mc guire et al.; licensee biomed central ltd.