title: Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.
abstract: Inherited and de novo mutations in the CARD14 gene promote the development of psoriasis, an inflammatory disease of the skin. Caspase recruitment domain-containing protein 14 (CARD14) is a member of the CARMA protein family that includes the structurally related CARD11 adaptor that mediates NF-κB activation by antigen receptors. We investigated the mechanism by which CARD14 mutation in psoriasis activates NF-κB. In contrast with wild-type CARD14, CARD14(E138A) and CARD14(G117S) psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10- and MALT1-dependent activation of NF-κB in keratinocytes. These alterations disrupted the inhibitory effect of the CARD14 linker region (LR) on NF-κB activation by facilitating BCL10 binding. Therefore, psoriasis mutations activated CARD14 by a mechanism analogous to oncogenic CARD11 mutations in non-Hodgkin B cell lymphomas. CARD14(E138A) also stimulated MALT1 paracaspase activity and activated both ERK1/2 and p38α MAP kinases. Inhibition of MALT1 with mepazine reduced CARD14(E138A)-induced expression of specific psoriasis-associated transcripts in keratinocytes. Our results establish the mechanism whereby gain-of-function CARD14 variants, which induce psoriatic disease in affected individuals, activate pro-inflammatory signalling.
authors.affiliation: National Heart and Lung Institute, Guy Scadding Building, Royal Brompton Campus, Imperial College London, London, SW3 6LY, U.K. The Francis Crick Institute-Mill Hill Laboratory, London, NW7 1AA, U.K.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Howes
authors.affiliation: The Francis Crick Institute-Mill Hill Laboratory, London, NW7 1AA, U.K.
authors.forename: Paul A
authors.initials: PA
authors.lastname: O'Sullivan
authors.affiliation: The Francis Crick Institute-Mill Hill Laboratory, London, NW7 1AA, U.K.
authors.forename: Felix
authors.initials: F
authors.lastname: Breyer
authors.affiliation: The Francis Crick Institute-Mill Hill Laboratory, London, NW7 1AA, U.K.
authors.forename: Ashavari
authors.initials: A
authors.lastname: Ghose
authors.affiliation: Department of Genetics, Washington University in Saint Louis, MO 63110, U.S.A.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.affiliation: National Heart and Lung Institute, Guy Scadding Building, Royal Brompton Campus, Imperial College London, London, SW3 6LY, U.K. a.bowcock@imperial.ac.uk steve.ley@crick.ac.uk.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowcock
authors.affiliation: The Francis Crick Institute-Mill Hill Laboratory, London, NW7 1AA, U.K. a.bowcock@imperial.ac.uk steve.ley@crick.ac.uk.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D048308:Mitogen-Activated Protein Kinase 14; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426243:CARD14 protein, human; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
keywords: NF-κB; caspase recruitment domain-containing protein 14 (CARD14); keratinocytes; mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1); psoriasis