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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- κ B. Recently, missense mutations in CARMA2 sh  have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2 sh  plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF- κ B activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2 sh , thereby inhibiting its capacity to activate NF- κ B by promoting lysosomal degradation of BCL10, which is essential for CARMA2 sh -mediated NF- κ B signaling. Remarkably, CARMA2 sh  mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2 sh  mutants to activate NF- κ B. 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.

cell death and disease

CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship