Dataset Information

The CARD14E138A phosphoproteome

ABSTRACT: Psoriasis is a chronic inflammatory disease of the skin for which current treatments are only partially effective. There is therefore an urgent need to develop novel therapies with higher efficacy through a better understanding of disease aetiology. Recently, it has been demonstrated that individuals with specific mutations in the gene encoding the adapter protein CARD14 have a high risk of developing psoriasis. Psoriasis associated CARD14 mutations result in enhanced activation of NF-kB transcription factors in keratinocytes. The CARD14/NF-kB axis may therefore be central in driving the pathogenesis of psoriasis. The aim of this project is to investigate the molecular mechanisms by which CARD14 activates the NF-kB pathway. Specifically, within this project, we aim to detail the downstream signalling pathways of a gain-of-function mutant CARD14 (E138A) via SILAC and mass spectrometry.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Keratinocyte

DISEASE(S): Psoriasis

SUBMITTER: Helen Flynn

LAB HEAD: Steven Ley

PROVIDER: PXD033009 | Pride | 2024-08-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	ICL8271-40-544722.zip	Other
	ICL8271A1RW10-40-543734.raw	Raw
	ICL8271A1RW13-40-543953.raw	Raw
	ICL8271A1RW14-40-543951.raw	Raw
	ICL8271A1RW15-40-543952.raw	Raw

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Publications

CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation.

O'Sullivan Paul A PA Aidarova Aigerim A Afonina Inna S IS Manils Joan J Thurston Teresa L M TLM Instrell Rachael R Howell Michael M Boeing Stefan S Ranawana Sashini S Herpels Melanie B MB Chetian Riwia R Bassa Matilda M Flynn Helen H Frith David D Snijders Ambrosius P AP Howes Ashleigh A Beyaert Rudi R Bowcock Anne M AM Ley Steven C SC

The Biochemical journal 20240901 18

Rare mutations in CARD14 promote psoriasis by inducing CARD14-BCL10-MALT1 complexes that activate NF-κB and MAP kinases. Here, the downstream signalling mechanism of the highly penetrant CARD14E138A alteration is described. In addition to BCL10 and MALT1, CARD14E138A associated with several proteins important in innate immune signalling. Interactions with M1-specific ubiquitin E3 ligase HOIP, and K63-specific ubiquitin E3 ligase TRAF6 promoted BCL10 ubiquitination and were essential for NF-κB an ...[more]

PMID: 39145956

Similar Datasets

Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. Keratinocytes were transfected with wildtype Cardsh or one of 16 Card14 mutations (17 total samples). The cells were collected and RNA extracted to determine the effect of these mutations compared to wildtype Card14. No replicates are included.