Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
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, 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 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 signaling.
Date Issued
2016-06-10
Date Acceptance
2016-04-11
Citation
Biochemical Journal, 2016, 473 (12), pp.1759-1768
ISSN
1470-8728
Publisher
Portland Press
Start Page
1759
End Page
1768
Journal / Book Title
Biochemical Journal
Volume
473
Issue
12
Copyright Statement
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
Sponsor
National Institutes of Health
Grant Number
7R01AR050266-07
Subjects
NF-κB
Caspase recruitment domain-containing protein 14 (CARD14)
Keratinocytes
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)
Psoriasis
Biochemistry & Molecular Biology
Biological Sciences
Medical And Health Sciences
Chemical Sciences
Publication Status
Published