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.

TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms

“…However, our studies suggest that Trim38 deficiency potentiated TLR3/4-mediated, but not TLR2-or TLR7-mediated, induction of cytokines. Finally, mouse gene-knockout studies demonstrated that Nap1 is not required for TLR3/4-mediated innate immune responses (32). Previously, we reported that another E3 ubiquitin ligase, WWP2, also targets TRIF for K48-linked polyubiquitination and proteasomal degradation (16).…”

5-Azacytidine-induced Protein 2 (AZI2) Regulates Bone Mass by Fine-tuning Osteoclast Survival

“…However, our previous knock-out study revealed that TANK is dispensable for the production of IFNs (16), but indispensable for the suppression of excessive osteoclast formation via the inhibition of TRAF6 activation (17). We also generated AZI2-and TBKBP1-deficient mice and revealed that both genes were dispensable for IFN production (18). However, to our surprise, AZI2-deficient bone marrow cells exhibited impaired GM-CSF-mediated dendritic cell differentiation in vitro (18).…”

“…Mice-AZI2-and TBKBP1-deficient mice were generated as described previously (18) and maintained in specific pathogenfree conditions. All animal experiments were performed in accordance with the approval of the Animal Research Committee of the Research Institute for Microbial Diseases (Osaka University, Osaka, Japan).…”

“…ϩ T proliferation was measured as described previously (18). LPS from Salmonella minnesota strain Re-595 was purchased from Sigma-Aldrich.…”

“…We also generated AZI2-and TBKBP1-deficient mice and revealed that both genes were dispensable for IFN production (18). However, to our surprise, AZI2-deficient bone marrow cells exhibited impaired GM-CSF-mediated dendritic cell differentiation in vitro (18). GM-CSF is involved in the survival, maturation, proliferation, and differentiation of myeloid cells including dendritic cells (19).…”