CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation
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 and MAP kinase activation. In contrast, the ubiquitin binding proteins A20 and ABIN1, both genetically associated with psoriasis development, negatively regulated signalling by inducing CARD14E138A turnover. CARD14E138A localized to early endosomes and was associated with the AP2 adaptor complex. AP2 function was required for CARD14E138A activation of mTOR complex 1 (mTORC1), which stimulated keratinocyte metabolism, but not for NF-κB nor MAP kinase activation. Furthermore, rapamycin ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis.
Authors
- A. Bowcock (ORCID: https://orcid.org/0000-0001-8691-9090)
- Joan Manils (ORCID: https://orcid.org/0000-0001-8429-1295)
- Ambrosius P. Snijders (ORCID: https://orcid.org/0000-0002-5416-8592)
- Aigerim Aidarova (ORCID: https://orcid.org/0000-0003-2149-6191)
- Steven C. Ley (ORCID: https://orcid.org/0000-0001-5911-9223)
- Inna S. Afonina (ORCID: https://orcid.org/0000-0001-8894-5305)
- David Frith
- Rachael Instrell (ORCID: https://orcid.org/0000-0002-4437-2952)
- Paul A. O’Sullivan
- Michael Howell (ORCID: https://orcid.org/0000-0003-0912-0079)
- Teresa L. M. Thurston (ORCID: https://orcid.org/0000-0001-6139-3723)
- Helen R. Flynn (ORCID: https://orcid.org/0000-0001-7002-9130)
- Stefan Boeing (ORCID: https://orcid.org/0000-0003-0495-5659)
- Ashleigh Howes (ORCID: https://orcid.org/0000-0001-9707-2067)
- Rudi Beyaert (ORCID: https://orcid.org/0000-0002-5704-582X)
- Sashini Ranawana
- Matilda Bassa
- Riwia Chetian
- Melanie B. Herpels
Institutions
- The Francis Crick Institute (GB)
- Ghent University (BE)
- Lung Institute (US)
- VIB-UGent Center for Inflammation Research (BE)
- University College London (GB)
- Imperial College London (GB)
- Universitat de Barcelona (ES)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Biochemical Journal
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1042/bcj20240058
- Citations
- 3
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- National Psoriasis Foundation
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council