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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes
Inna S Afonina1, Elien Van Nuffel1, Griet Baudelet1
1Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Insights
Mutations in CARD14 activate inflammatory pathways via paracaspase MALT1. Inhibiting MALT1 reduces cytokine expression, suggesting MALT1 as a therapeutic target for psoriasis.
Area of Science:
- Immunology
- Molecular Biology
- Dermatology
Background:
- CARD14 mutations are linked to psoriasis susceptibility.
- CARD14 regulates NF-κB activation in the epidermis.
- The full spectrum of CARD14 signaling and its regulation is not fully understood.
Purpose of the Study:
- To investigate CARD14's role in activating signaling pathways beyond NF-κB.
- To elucidate the biochemical mechanisms underlying CARD14 function.
- To explore the therapeutic potential of targeting CARD14-MALT1 interactions in psoriasis.
Main Methods:
- Investigated CARD14 activation of p38 and JNK MAP kinase pathways.
- Assessed the dependence of CARD14 signaling on paracaspase MALT1.
- Examined CARD14's physical interaction with MALT1 and its effect on MALT1 proteolytic activity.
- Studied the impact of MALT1 deficiency and pharmacological inhibition on CARD14-induced gene expression in keratinocytes.
Main Results:
- CARD14 activates p38 and JNK MAP kinase pathways, dependent on MALT1.
- CARD14 physically interacts with MALT1, enhancing its proteolytic activity and inflammatory gene expression.
- Psoriasis-associated CARD14 mutations amplify these effects.
- MALT1 inhibition significantly reduces pathogenic mutant CARD14-induced cytokine and chemokine expression in keratinocytes.
Conclusions:
- CARD14 activates multiple inflammatory signaling pathways through MALT1.
- MALT1 plays a critical role in CARD14-mediated signaling in keratinocytes.
- MALT1 represents a promising therapeutic target for psoriasis treatment.
Abstract:
Mutations in CARD14 have recently been linked to psoriasis susceptibility. CARD14 is an epidermal regulator of NF-κB activation. However, the ability of CARD14 to activate other signaling pathways as well as the biochemical mechanisms that mediate and regulate its function remain to be determined. Here, we report that in addition to NF-κB signaling, CARD14 activates p38 and JNK MAP kinase pathways, all of which are dependent on the paracaspase MALT1. Mechanistically, we demonstrate that CARD14 physically interacts with paracaspase MALT1 and activates MALT1 proteolytic activity and inflammatory gene expression, which are enhanced by psoriasis-associated CARD14 mutations. Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14-induced cytokine and chemokine expression in human primary keratinocytes. Collectively, our findings demonstrate a novel role for MALT1 in CARD14-induced signaling and indicate MALT1 as a valuable therapeutic target in psoriasis.
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