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

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Rare mutations in CARD14 are linked to psoriasis development.
• CARD14 mutations promote psoriasis by activating nuclear factor-kappa B (NF-κB) and mitogen-activated protein (MAP) kinases through CARD14-BCL10-MALT1 complexes.
• The specific downstream signaling mechanisms of CARD14 mutations require further elucidation.

Purpose of the Study:

• To elucidate the downstream signaling mechanisms of the CARD14E138A mutation.
• To investigate the role of protein interactions and ubiquitination in CARD14-mediated signaling.
• To explore the potential therapeutic implications of targeting mTORC1 in CARD14-dependent psoriasis.

Main Methods:

• Co-immunoprecipitation assays to identify protein interactions.
• Ubiquitination assays to assess protein modification.
• Immunofluorescence microscopy to determine protein localization.
• In vivo mouse models to evaluate therapeutic efficacy.

Main Results:

• CARD14E138A interacts with HOIP and TRAF6, promoting BCL10 ubiquitination essential for NF-κB and MAP kinase activation.
• A20 and ABIN1 negatively regulate CARD14E138A signaling by inducing its turnover.
• CARD14E138A localizes to early endosomes and requires AP2 complex for mTORC1 activation, stimulating keratinocyte metabolism.
• Rapamycin treatment ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice.

Conclusions:

• The CARD14E138A mutation activates distinct signaling pathways, including NF-κB, MAP kinases, and mTORC1.
• Ubiquitination and deubiquitination processes play critical roles in regulating CARD14 signaling.
• Targeting mTORC1 represents a promising therapeutic strategy for CARD14-dependent psoriasis.