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

Biochem J. 2024 Sep 18;481(18):1143-1171. doi: 10.1042/BCJ20240058.

Abstract

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.

Keywords: ABIN1; CARD14; LUBAC; NF-κB; a20; keratinocytes; mTOR; psoriasis.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein / genetics
  • B-Cell CLL-Lymphoma 10 Protein / metabolism
  • CARD Signaling Adaptor Proteins* / genetics
  • CARD Signaling Adaptor Proteins* / metabolism
  • Cell Proliferation*
  • Endosomes* / metabolism
  • Guanylate Cyclase
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Keratinocytes* / metabolism
  • Mechanistic Target of Rapamycin Complex 1* / genetics
  • Mechanistic Target of Rapamycin Complex 1* / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein Transport
  • Psoriasis / genetics
  • Psoriasis / metabolism
  • Psoriasis / pathology
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • CARD Signaling Adaptor Proteins
  • CARD14 protein, human
  • Guanylate Cyclase
  • Intracellular Signaling Peptides and Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins
  • NF-kappa B
  • Tifab protein, human
  • TNF Receptor-Associated Factor 6
  • Ubiquitin-Protein Ligases
  • Card14 protein, mouse