Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation
journal contributionposted on 2020-08-05, 16:58 authored by Ashleigh Howes, Paul A O'Sullivan, Felix Breyer, Ashavari Ghose, Li Cao, Daniel Krappmann, Anne M Bowcock, Steven C Ley
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, 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 (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. 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 signalling.
NF-κBcaspase recruitment domain-containing protein 14 (CARD14)keratinocytesmucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)psoriasisAdaptor Proteins, Signal TransducingB-Cell CLL-Lymphoma 10 ProteinCARD Signaling Adaptor ProteinsCaspasesCell LineGuanylate CyclaseHumansImmunoprecipitationKeratinocytesMAP Kinase Signaling SystemMembrane ProteinsMitogen-Activated Protein Kinase 14Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 ProteinMutationNF-kappa BNeoplasm ProteinsProtein BindingPsoriasisRNA, Small InterferingSignal TransductionLey FC001103GSK06 Biological Sciences11 Medical and Health Sciences03 Chemical SciencesBiochemistry & Molecular Biology