Abstract
The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2sh plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-κB signaling. Remarkably, CARMA2sh mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2sh mutants to activate NF-κB. Our work elucidates a fundamental signaling mechanism operating in human keratinocytes and opens to novel potential tools for the therapeutical treatment of human skin disorders.
Highlights
Psoriasis is a debilitating skin disease affecting ~ 2–3% of human population.[1]
Most of the studies conducted to elucidate the functional role of CARMA2 and its mutated forms associated with psoriasis have been carried out using CARMA2sh,[6,7,8,9,11] the prominent isoform of CARMA2 expressed in the human skin.[7,10]
Yeast colonies were scored as positive when a growth developed within 24–36 h; a negative was scored when growth failed to develop within 1 week performed a yeast two-hybrid screen using as a bait CARMA2sh fused to the GAL4 DNA-binding domain
Summary
Psoriasis is a debilitating skin disease affecting ~ 2–3% of human population.[1]. The disease is considered to have key genetic underpinnings, and genome-wide association studies and meta-analysis have identified more than 40 susceptibility loci for psoriasis.[1,2,3,4,5] Recently, missense mutations in the CARD14/CARMA2/Bimp[2] (CARMA2) gene products have been shown to dominantly transmit the psoriatic trait with high penetrancy.[6,7,8] Mutations in CARMA2 are found in individuals affected by familial pityriasis rubra pilaris (PRP), a skin disorder phenotypically related to psoriasis.[9]. We show that in human keratinocytes the CBM complex plays an essential role in the signal transduction pathway that links pathogen-associated molecular patterns (PAMPs) recognition on the cell membrane to NF-κB activation
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