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, CARD14E138A and CARD14G117S 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. CARD14E138A also stimulated MALT1 paracaspase activity and activated both ERK1/2 and p38α MAP kinases. Inhibition of MALT1 with mepazine reduced CARD14E138A-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.
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K-Ras4B membrane-anchored dimers in the cell. Dimerization can take place through helical (left) and beta-sheet (right) interfaces. The major (front) and minor (back) conformations are shown. For further details please see pp. 1719–1732. Image kindly provided by Ruth Nussinov. - PDF Icon PDF LinkFront Matter
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Research Article|
June 10 2016
Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation
Ashleigh Howes;
Ashleigh Howes
*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.
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Paul A. O'Sullivan;
Paul A. O'Sullivan
†The Francis Crick Institute–Mill Hill Laboratory, London, NW7 1AA, U.K.
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Felix Breyer;
Felix Breyer
†The Francis Crick Institute–Mill Hill Laboratory, London, NW7 1AA, U.K.
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Ashavari Ghose;
Ashavari Ghose
†The Francis Crick Institute–Mill Hill Laboratory, London, NW7 1AA, U.K.
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Li Cao;
Li Cao
‡Department of Genetics, Washington University in Saint Louis, MO 63110, U.S.A.
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Daniel Krappmann;
Daniel Krappmann
§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
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Anne M. Bowcock;
Anne M. Bowcock
1
*National Heart and Lung Institute, Guy Scadding Building, Royal Brompton Campus, Imperial College London, London, SW3 6LY, U.K.
1Correspondence may be addressed to either of these authors (email a.bowcock@imperial.ac.uk or steve.ley@crick.ac.uk).
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Steven C. Ley
Steven C. Ley
1
†The Francis Crick Institute–Mill Hill Laboratory, London, NW7 1AA, U.K.
1Correspondence may be addressed to either of these authors (email a.bowcock@imperial.ac.uk or steve.ley@crick.ac.uk).
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Publisher: Portland Press Ltd
Received:
March 30 2016
Revision Received:
April 08 2016
Accepted:
April 11 2016
Accepted Manuscript online:
April 12 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (12): 1759–1768.
Article history
Received:
March 30 2016
Revision Received:
April 08 2016
Accepted:
April 11 2016
Accepted Manuscript online:
April 12 2016
Citation
Ashleigh Howes, Paul A. O'Sullivan, Felix Breyer, Ashavari Ghose, Li Cao, Daniel Krappmann, Anne M. Bowcock, Steven C. Ley; Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation. Biochem J 15 June 2016; 473 (12): 1759–1768. doi: https://doi.org/10.1042/BCJ20160270
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