Imperial College London

ProfessorAnneBowcock

Faculty of MedicineNational Heart & Lung Institute

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 1511a.bowcock

 
 
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Location

 

Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Howes:2016:10.1042/BCJ20160270,
author = {Howes, A and O'Sullivan, PA and Breyer, F and Ghose, A and Cao, L and Krappmann, D and Bowcock, AM and Ley, SC},
doi = {10.1042/BCJ20160270},
journal = {Biochemical Journal},
pages = {1759--1768},
title = {Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation},
url = {http://dx.doi.org/10.1042/BCJ20160270},
volume = {473},
year = {2016}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Inherited and <em>de novo</em> mutations in the <em>CARD14</em> 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 <em>CARD14 </em>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.
AU - Howes,A
AU - O'Sullivan,PA
AU - Breyer,F
AU - Ghose,A
AU - Cao,L
AU - Krappmann,D
AU - Bowcock,AM
AU - Ley,SC
DO - 10.1042/BCJ20160270
EP - 1768
PY - 2016///
SN - 1470-8728
SP - 1759
TI - Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation
T2 - Biochemical Journal
UR - http://dx.doi.org/10.1042/BCJ20160270
UR - http://hdl.handle.net/10044/1/31103
VL - 473
ER -