title: Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis.
abstract: 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.
authors.forename: Conor
authors.initials: C
authors.lastname: Mc Guire
authors.forename: Lynn
authors.initials: L
authors.lastname: Elton
authors.forename: Peter
authors.initials: P
authors.lastname: Wieghofer
authors.forename: Jens
authors.initials: J
authors.lastname: Staal
authors.forename: Sofie
authors.initials: S
authors.lastname: Voet
authors.forename: Annelies
authors.initials: A
authors.lastname: Demeyer
authors.forename: Daniel
authors.initials: D
authors.lastname: Nagel
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Technologiepark 927, B-9052 Ghent, Belgium. rudi.beyaert@irc.vib-ugent.be.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy; D005500:Follow-Up Studies; D008213:Lymphocyte Activation; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000188:drug therapy; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity; D010640:Phenothiazines / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D010640:Phenothiazines; C445081:myelin oligodendrocyte glycoprotein (35-55); C100190:mepazine; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein