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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
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Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation

Ashleigh Howes1, Paul A O'Sullivan2, Felix Breyer2

  • 1National Heart and Lung Institute, Guy Scadding Building, Royal Brompton Campus, Imperial College London, London, SW3 6LY, U.K. The Francis Crick Institute-Mill Hill Laboratory, London, NW7 1AA, U.K.

The Biochemical Journal
|April 14, 2016
PubMed

Insights

Mutations in the CARD14 gene drive psoriasis by constitutively activating NF-κB signaling in skin cells. This mechanism involves CARD14 interacting with BCL10 and MALT1, promoting inflammation.

Area of Science:

  • Immunology
  • Dermatology
  • Molecular Biology

Background:

  • Psoriasis is an inflammatory skin disease linked to CARD14 gene mutations.
  • CARD14 is structurally similar to CARD11, an adaptor protein involved in NF-κB activation.

Purpose of the Study:

  • To elucidate the mechanism by which CARD14 mutations activate NF-κB in psoriasis.
  • To compare CARD14's role in psoriasis to CARD11's role in lymphomas.

Main Methods:

  • Investigated CARD14 mutants (E138A, G117S) and their interaction with BCL10 and MALT1.
  • Assessed NF-κB activation in keratinocytes.
  • Examined MALT1 paracaspase activity and MAP kinase activation (ERK1/2, p38α).
  • Utilized MALT1 inhibition with mepazine to analyze downstream transcript expression.

Main Results:

  • Psoriasis-associated CARD14 mutants constitutively interacted with BCL10 and MALT1, activating NF-κB in keratinocytes.
  • Mutations disrupted the inhibitory effect of CARD14's linker region, facilitating BCL10 binding.
  • CARD14(E138A) enhanced MALT1 activity and activated ERK1/2 and p38α MAP kinases.
  • MALT1 inhibition reduced the expression of psoriasis-associated transcripts.

Conclusions:

  • Gain-of-function CARD14 variants activate pro-inflammatory signaling through a mechanism analogous to oncogenic CARD11 mutations.
  • This study clarifies how CARD14 mutations lead to psoriatic disease.
  • Targeting MALT1 may offer a therapeutic strategy for psoriasis.

Keywords:
NF-κBcaspase recruitment domain-containing protein 14 (CARD14)keratinocytesmucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)psoriasis

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