title: Critical role of AZI2 in GM-CSF-induced dendritic cell differentiation.
abstract: TNFR-associated factor family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1) is critical for the activation of IFN regulatory factor 3 and type I IFN production upon virus infection. A set of TBK1-binding proteins, 5-azacytidine-induced gene 2 (AZI2; also known as NAP1), TANK, and TBK1-binding protein 1 (TBKBP1), have also been implicated in the production of type I IFNs. Among them, TANK was found to be dispensable for the responses against virus infection. However, physiological roles of AZI2 and TBKBP1 have yet to be clarified. In this study, we found that none of these TBK1-binding proteins is critical for type I IFN production in mice. In contrast, AZI2, but not TBKBP1, is critical for the differentiation of conventional dendritic cells (cDCs) from bone marrow cells in response to GM-CSF. AZI2 controls GM-CSF-induced cell cycling of bone marrow cells via TBK1. GM-CSF-derived DCs from AZI2-deficient mice show severe defects in cytokine production and T cell activation both in vitro and in vivo. Reciprocally, overexpression of AZI2 results in efficient generation of cDCs, and the cells show enhanced T cell activation in response to Ag stimulation. Taken together, AZI2 expression is critical for the generation of cDCs by GM-CSF and can potentially be used to increase the efficiency of immunization by cDCs.
authors.affiliation: Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukasaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ori
authors.forename: Tatsukata
authors.initials: T
authors.lastname: Kawagoe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Kenta
authors.initials: K
authors.lastname: Maruyama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Okazaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kozaki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Imamura
authors.forename: Sarang
authors.initials: S
authors.lastname: Tartey
authors.forename: Takashi
authors.initials: T
authors.lastname: Mino
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D000941:Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: C582344:AZI2 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D016207:Cytokines; D008565:Membrane Proteins; D051193:Toll-Like Receptors; C084881:flt3 ligand protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases