RRC ID 47445
Author Yamamura K, Uruno T, Shiraishi A, Tanaka Y, Ushijima M, Nakahara T, Watanabe M, Kido-Nakahara M, Tsuge I, Furue M, Fukui Y.
Title The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction.
Journal Nat Commun
Abstract Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.
Volume 8
Pages 13946
Published 2017-1-9
DOI 10.1038/ncomms13946
PII ncomms13946
PMID 28067314
PMC PMC5228069
MeSH Active Transport, Cell Nucleus Animals Aryl Hydrocarbon Receptor Nuclear Translocator / genetics Aryl Hydrocarbon Receptor Nuclear Translocator / immunology Basic Helix-Loop-Helix Transcription Factors / deficiency Basic Helix-Loop-Helix Transcription Factors / genetics* Basic Helix-Loop-Helix Transcription Factors / immunology CD4-Positive T-Lymphocytes / immunology* CD4-Positive T-Lymphocytes / pathology Cell Nucleus / immunology Cell Nucleus / metabolism Cytosol / immunology Cytosol / metabolism Dermatitis, Atopic / genetics* Dermatitis, Atopic / immunology Dermatitis, Atopic / pathology Disease Models, Animal Female Gene Expression Regulation Guanine Nucleotide Exchange Factors / deficiency Guanine Nucleotide Exchange Factors / genetics* Guanine Nucleotide Exchange Factors / immunology Heterozygote Immunoglobulin E / genetics Immunoglobulin E / immunology Interleukins / genetics* Interleukins / immunology Male Mice Mice, Knockout Promoter Regions, Genetic Protein Transport Signal Transduction Sp1 Transcription Factor / genetics Sp1 Transcription Factor / immunology
IF 12.121
Times Cited 24
Mice RBRC02711