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Mc Guire, C.* ; Elton, L.* ; Wieghofer, P.* ; Staal, J.* ; Voet, S.* ; Demeyer, A.* ; Nagel, D. ; Krappmann, D. ; Prinz, M.* ; Beyaert, R.* ; van Loo, G.*

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

J. Neuroinflamm. 11:124 (2014)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Multiple Sclerosis ; Experimental Autoimmune Encephalomyelitis ; Malt1 ; Mepazine ; Demyelination; Nf-kappa-b; Autoimmune-mediated Demyelination; Paracaspase Malt1; Abc-dlbcl; Activation; Cleavage; Lymphoma; Immune; A20

ISSN (print) / ISBN 1742-2094

e-ISSN 1742-2094

Journal Journal of Neuroinflammation

Quellenangaben Volume: 11, Issue: 1, Article Number: 124

Publisher BioMed Central

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Signaling and Translation (SAT)