N-Myc and STAT interactor as a context-dependent switch in innate antiviral immunity.

N-Myc and STAT interactor (NMI), initially identified as a Myc- and STAT-associated protein, is increasingly recognized as a regulatory node in innate antiviral immunity. Current evidence indicates that NMI does not exert a fixed antiviral or proviral effect. Instead, its functional output is shaped by interacting partners, signaling pathway context, subcellular localization, and stage of infection. In selected acute RNA virus models, NMI suppresses IRF7-dependent type I interferon (IFN-I) signaling. In the IAV model, this involves an NMI-IFP35 complex coupled to the TRIM21-IRF7 axis that promotes IRF7 degradation, suppresses IFN-I responses, and thereby facilitates viral replication. In foamy virus infection, by contrast, NMI directly binds the viral transactivator Tas, retains it in the cytoplasm, and suppresses viral transcription, thus acting as a host restriction factor. In human cytomegalovirus (HCMV) infection, NMI appears to function as a host pathway component targeted by viral antagonism, as the viral protein UL23 interferes with the NMI-STAT1/IFN-γ axis and dampens antiviral gene expression. In addition, extracellular NMI and IFP35 can function as damage-associated molecular patterns that amplify inflammation. Together, these findings support the view that NMI acts as a context-dependent molecular switch rather than a unidirectional effector in innate antiviral immunity.