Dataset Information

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-?B. 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-?B activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-?B by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-?B 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-?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.

SUBMITTER: Scudiero I

PROVIDER: S-EPMC5386493 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Scudiero Ivan I Mazzone Pellegrino P D'Andrea Luca E LE Ferravante Angela A Zotti Tiziana T Telesio Gianluca G De Rubis Gabriele G Reale Carla C Pizzulo Maddalena M Muralitharan Shanmugakonar S Vito Pasquale P Stilo Romania R

Cell death & disease 20170223 2

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 c ...[more]

PMID: 28230860

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Project description:MyD88 is an adaptor protein in Toll-like receptor and interleukin 1 receptor mediated signaling pathways that plays an essential role in activation of immune responses following pathogen recognition. We investigate that role in the zebrafish embryo model by using a zebrafish mutant line that contains a premature stop condon in the gene encoding MyD88, leading to a truncated protein that lacks domains important for its normal function. We infected these MyD88 mutants and wildtype individuals with Salmonella typhimurium and Edwardsiella tarda to compare the resulting immune response by transcriptome profiling on total RNA isolated from single embryos. The data derived from these microarray experiments confirms the vital role of MyD88 in pathogen recognition and provides many leads for further research. This microarray study was designed to determine the effect of a truncation of the MyD88 protein on the innate immune response of zebrafish embryos during infection with Salmonella typhimurium and Edwardsiella tarda. Embryos used in this study are derived from an incross between parents heterozygous for the mutation. Both homozygous mutants and their wildtype siblings were selected by genotyping after being injected with the bacteria or PBS as control. RNA was isolated from single embryos and each treatment group consisted of three embryos: (1) Homozygous mutants injected with PBS 8 hours post infection (hpi), (2) wildtype siblings injected with PBS 8hpi, (3) S. typhimurium-infected homozygous mutants 8hpi, (4) S. typhimurium-infected wildtype siblings 8hpi, (5) Homozygous mutants injected with PBS 8 hours post infection (hpi) (E.tarda control), (6) wildtype siblings injected with PBS 8hpi (E. tarda control), (7) E. tarda-infected homozygous mutants 8hpi, (8) E. tarda-infected wildtype siblings 8hpi. Embryos were grown at 28.5M-bM-^@M-^S30M-BM-0C in egg water and manually dechorionated at 24 hours post fertilization (hpf). Subsequently, embryos were infected at 28 hpf by micro-injecting 200 colony forming units (CFU) of S. typhimurium SL1027 or E. Tarda FL-F60, or were mock-injected with buffer as a control. After injections embryos were transferred into fresh egg water and incubated for 8 h or 4 days at 28M-BM-0C. After the incubation period, single embryos were snap-frozen in liquid nitrogen and RNA was isolated for microarray analysis. All treatment groups were analyzed using a common reference approach.

Dataset Information

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

Publications

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

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