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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)
Postprint DOI PMC
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Biochemical Journal / Reviews
Quellenangaben Band: 473, Heft: 12, Seiten: 1759-1768 Artikelnummer: , Supplement: ,
Verlag Portland Press
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)