title: TAK1 is a central mediator of NOD2 signaling in epidermal cells.
abstract: Muramyl dipeptide (MDP) is a peptidoglycan moiety derived from commensal and pathogenic bacteria, and a ligand of its intracellular sensor NOD2. Mutations in NOD2 are highly associated with Crohn disease, which is characterized by dysregulated inflammation in the intestine. However, the mechanism linking abnormality of NOD2 signaling and inflammation has yet to be elucidated. Here we show that transforming growth factor beta-activated kinase 1 (TAK1) is an essential intermediate of NOD2 signaling. We found that TAK1 deletion completely abolished MDP-NOD2 signaling, activation of NF-kappaB and MAPKs, and subsequent induction of cytokines/chemokines in keratinocytes. NOD2 and its downstream effector RICK associated with and activated TAK1. TAK1 deficiency also abolished MDP-induced NOD2 expression. Because mice with epidermis-specific deletion of TAK1 develop severe inflammatory conditions, we propose that TAK1 and NOD2 signaling are important for maintaining normal homeostasis of the skin, and its ablation may impair the skin barrier function leading to inflammation.
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695.
authors.forename: Emily
authors.initials: E
authors.lastname: Omori
authors.affiliation: Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, 464-8602 Japan; Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695. Electronic address: Jun_Tsuji@ncsu.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D015151:Immunoblotting; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000119:Acetylmuramyl-Alanyl-Isoglutamine; D019743:Chemokines, CXC; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7