Abstract
Aryl hydrocarbon receptor (AhR) interacting protein (AIP) suppresses type I IFN production by interacting with and preventing the nuclear translocation of the transcription factor IRF7. The kinase TBK1 phosphorylates AIP to promote IRF7 binding and the inhibition of the type I interferon (IFN) response. However, it is unknown if AIP expression in innate immune cells is important to suppress type I IFN in the context of RNA virus infection in vitro and in vivo. In this study we generated myeloid cell-specific AIP conditional knockout mice (Aip (fl/fl)xLysM-Cre) to investigate AIP regulation of innate immune signaling in myeloid cells. Bone marrow-derived macrophages (BMDMs) from Aip (fl/fl)xLysM-Cre mice had diminished viral replication and increased production of IFNα/β and IL-6 in response to RNA virus infection. AIP-deficient macrophages exhibited increased IRF7 expression and impaired virus-induced IRF7 degradation. AIP interacted with the E3 ubiquitin ligase SOCS1 and enhanced SOCS1 stability and its interaction with IRF7 to promote the proteasomal degradation of IRF7. Aip (fl/fl)xLysM-Cre mice exhibited improved survival upon influenza A virus (IAV) infection compared to control mice. Together, these results indicate that myeloid cell-specific AIP suppresses the innate immune response by targeting IRF7.