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AuthorScudiero, Ivan
AuthorMazzone, Pellegrino
AuthorD'Andrea, Luca E.
AuthorFerravante, Angela
AuthorZotti, Tiziana
AuthorTelesio, Gianluca
AuthorDe Rubis, Gabriele
AuthorReale, Carla
AuthorPizzulo, Maddalena
AuthorMuralitharan, Shanmugakonar
AuthorVito, Pasquale
AuthorStilo, Romania
Available date2017-05-11T09:44:05Z
Publication Date2017-02-23
Publication NameCell Death and Diseaseen_US
Identifierhttp://dx.doi.org/10.1038/cddis.2017.51
CitationScudiero, Ivan; Mazzone, Pellegrino; D'Andrea, Luca E.; et al. "CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship" Cell Death and Disease (2017) 8, e2627; Published online 23 February 2017
ISSN2041-4889
URIhttp://hdl.handle.net/10576/5489
AbstractThe 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.
SponsorThis publication was made possible by a NPRP award (NPRP 7-1189-3-304) from the Qatar National Research Fund (a member of The Qatar Foundation).
Languageen
PublisherNature
SubjectNF-kB
SubjectPsoriasis
SubjectKeratinocytes
SubjectCARMA2sh
SubjectULK2
TitleCARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship
TypeArticle
Volume Number8


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