The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
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.
Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Inna S
IS
Afonina
Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Elien
E
Van Nuffel
Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Griet
G
Baudelet
Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Yasmine
Y
Driege
Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Marja
M
Kreike
Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Jens
J
Staal
Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium Rudi.Beyaert@irc.vib-ugent.be.
Rudi
0000-0002-5704-582X
R
Beyaert
D015415:Biomarkers; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002384:Catalysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D015415:Biomarkers; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426243:CARD14 protein, human; D006162:Guanylate Cyclase
CARD14 signaling pathway; MALT1; inflammation; proteolytic activity; psoriasis