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Howes, A.* ; O'Sullivan, P.A.* ; Breyer, F.* ; Ghose, A.* ; Cao, L.* ; Krappmann, D. ; Bowcock, A.M.* ; Ley, S.C.*

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

Biochem. J. 473, 1759-1768 (2016)

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	Open Access Green

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Inherited and de novo mutations in the CARD14 gene promote the development of psoriasis, an inflammatory disease of the skin. 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 to 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 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 signaling.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Card14 ; Malt1 ; Keratinocytes ; Nuclear Factor Kappab ; Psoriasis; Responsive Inhibitory Domain; Innate Immunity; Arthritis; Malt1; Phosphorylation; Identification; Regnase-1; Proteins; Cleavage; Bcl10

ISSN (print) / ISBN 0264-6021

e-ISSN 1470-8728

Journal Biochemical Journal / Reviews

Quellenangaben Volume: 473, Issue: 12, Pages: 1759-1768

Publisher Portland Press

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

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