Acts as a signaling pathway regulator involved in innate immune system response (PubMed:9989503, PubMed:26342464, PubMed:29038465, PubMed:29350881). In response to interleukin 2/IL2 and interferon IFN-gamma/IFNG, interacts with signal transducer and activator of transcription/STAT which activate the transcription of downstream genes involved in a multitude of signals for development and homeostasis (PubMed:9989503, PubMed:29377960). Enhances the recruitment of CBP/p300 coactivators to STAT1 and STAT5, resulting in increased STAT1- and STAT5-dependent transcription (PubMed:9989503). In response to interferon IFN-alpha, associates in a complex with signaling pathway regulator IFI35 to regulate immune response; the complex formation prevents proteasome-mediated degradation of IFI35 (PubMed:10779520, PubMed:10950963). In complex with IFI35, inhibits virus-triggered type I IFN-beta production when ubiquitinated by ubiquitin-protein ligase TRIM21 (PubMed:26342464). In complex with IFI35, negatively regulates nuclear factor NF-kappa-B signaling by inhibiting the nuclear translocation, activation and transcription of NF-kappa-B subunit p65/RELA, resulting in the inhibition of endothelial cell proliferation, migration and re-endothelialization of injured arteries (PubMed:29350881). Negatively regulates virus-triggered type I interferon/IFN production by inducing proteosome-dependent degradation of IRF7, a transcriptional regulator of type I IFN, thereby interfering with cellular antiviral responses (By similarity). Beside its role as an intracellular signaling pathway regulator, also functions extracellularly as damage-associated molecular patterns (DAMPs) to promote inflammation, when actively released by macrophage to the extracellular space during cell injury or pathogen invasion (PubMed:29038465). Macrophage-secreted NMI activates NF-kappa-B signaling in adjacent macrophages through Toll-like receptor 4/TLR4 binding and activation, thereby inducing NF-kappa-B translocation from the cytoplasm into the nucleus which promotes the release of pro-inflammatory cytokines (PubMed:29038465). Interacts with MYCN and MYC, as well as with other transcription factors with a Zip, HLH or a HLH-Zip motif (PubMed:8668343). Interacts with all STAT proteins except STAT2 (PubMed:9989503). Interacts with IRF7, the interaction is direct and leads to the inhibition of IRF7-mediated type I IFN production (By similarity). Interacts (via coiled-coil domain) with TRIM21 (via the SPRY domain); the interaction leads to 'Lys-63'-linked ubiquitination of NMI (PubMed:26342464). Interacts with IFI35; the interaction is direct and is facilitated by TRIM21 (PubMed:10779520, PubMed:10950963, PubMed:26342464). Interacts with TLR4; the interaction is direct and leads to NF-kappa-B activation (PubMed:29038465). (Microbial infection) Interacts with human cytomegalovirus protein UL23; this interaction inhibits NMI-mediated transcription of interferon-gamma stimulated genes. Cytoplasmic NMI localizes in punctate granular structures (PubMed:9781816, PubMed:10950963). Nuclear localization increased following IFN-alpha treatment (PubMed:9781816, PubMed:10950963). Extracelullar following secretion by macrophage (PubMed:29038465). Expressed in adult spleen, liver, and kidney (PubMed:9781816). Expressed in fetal thymus, liver, placenta, spleen, lung, and kidney but not brain (PubMed:9781816). Expressed in macrophages (PubMed:29038465). Up-regulated by interferon IFN-alpha and IFN-gamma (PubMed:9781816, PubMed:9989503, PubMed:10779520, PubMed:10950963). Induced by IL2/interleukin-2 (PubMed:9989503). Induced by Sendai virus (PubMed:26342464). The coiled-coil domain is necessary for interaction with TRIM21 and for TRIM21-mediated ubiquitination of NMI. The NID domains are necessary for the interaction with IFI35 (PubMed:26342464). The NID domain 1 is necessary and IRF7 (By similarity). Ubiquitinated. 'Lys-63'-linked ubiquitination by TRIM21 promotes interaction with IFI35 and inhibits virus-triggered type I IFN-beta production. Belongs to the NMI family. The TRIM21-mediated ubiquitinated residue is not conserved in mice, therefore it remains unclear whether the physiological role of NMI ubiquitination is preserved throughout mammals.