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Biochem J. 2016 Jun 15;473(12):1759-68. doi: 10.1042/BCJ20160270. Epub 2016 Apr 12.

Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.

Author information

1
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.
2
The Francis Crick Institute-Mill Hill Laboratory, London, NW7 1AA, U.K.
3
Department of Genetics, Washington University in Saint Louis, MO 63110, U.S.A.
4
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.
5
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.
6
The Francis Crick Institute-Mill Hill Laboratory, London, NW7 1AA, U.K. a.bowcock@imperial.ac.uk steve.ley@crick.ac.uk.

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.

KEYWORDS:

NF-κB; caspase recruitment domain-containing protein 14 (CARD14); keratinocytes; mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1); psoriasis

PMID:
27071417
PMCID:
PMC5810350
DOI:
10.1042/BCJ20160270
[Indexed for MEDLINE]
Free PMC Article

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