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bioRxiv · 10.1101/2025.06.30.662398

The aryl hydrocarbon receptor interacting protein suppresses RNA virus-induced type I IFN and IL-6 in mouse macrophages

Kazzaz, S. A.·Umstead, T. M.·Chroneos, Z. C.·Harhaj, E. W.
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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 (Aipfl/flxLysM-Cre) to investigate AIP regulation of innate immune signaling in myeloid cells. Bone marrow-derived macrophages (BMDMs) from Aipfl/flxLysM-Cre mice had diminished viral replication and increased production of IFN/b 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. Aipfl/flxLysM-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.

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Kazzaz, S. A., Umstead, T. M., Chroneos, Z. C., Harhaj, E. W.. 2025-07-02. The aryl hydrocarbon receptor interacting protein suppresses RNA virus-induced type I IFN and IL-6 in mouse macrophages. https://doi.org/10.1101/2025.06.30.662398

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