title: CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship.
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.
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Scudiero
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Mazzone
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.
authors.forename: Luca E
authors.initials: LE
authors.lastname: D'Andrea
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Ferravante
authors.affiliation: Genus Biotechnology, Universita' del Sannio, Via Port'Arsa 10, Benevento, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Zotti
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Telesio
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: De Rubis
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Reale
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Pizzulo
authors.affiliation: Laboratory Animal Research Centre, Qatar University, PO Box 2713, Doha, Qatar.
authors.forename: Shanmugakonar
authors.initials: S
authors.lastname: Muralitharan
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.|Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port'Arsa 10, Benevento, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Vito
authors.affiliation: Biogem, Via Camporeale, Ariano Irpino, Italy.|Dipartimento di Scienze e Tecnologie, Università del Sannio, Via Port'Arsa 10, Benevento, Italy.
authors.forename: Romania
authors.initials: R
authors.lastname: Stilo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D002460:Cell Line; D006162:Guanylate Cyclase / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000069452:Pathogen-Associated Molecular Pattern Molecules / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011565:Psoriasis / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D000069452:Pathogen-Associated Molecular Pattern Molecules; D017346:Protein Serine-Threonine Kinases; C541703:Ulk2 protein, human; C426243:CARD14 protein, human; D006162:Guanylate Cyclase