N‐MYC‐interacting protein enhances type II interferon signaling by inhibiting STAT1 sumoylation

Signaling desensitization is key to limiting signal transduction duration and intensity. Signal transducer and activator of transcription 1 (STAT1) can mediate type II interferon (IFNγ)‐induced immune responses, which are enhanced and inhibited by STAT1 phosphorylation and sumoylation, respectively. Here, we identified an N‐MYC interacting protein, NMI, which can enhance STAT1 phosphorylation and STAT1‐mediated IFNγ immune responses by binding and sequestering the E2 SUMO conjugation enzyme, UBC9, and blocking STAT1 sumoylation. NMI facilitates UBC9 nucleus‐to‐cytoplasm translocation in response to IFNγ, thereby inhibiting STAT1 sumoylation. STAT1 phosphorylation at Y701 and sumoylation at K703 are mutually exclusive modifications that regulate IFNγ‐dependent transcriptional responses. NMI could not alter the phosphorylation level of sumoylation‐deficient STAT1 after IFNγ treatment. Thus, IFNγ signaling is modulated by NMI through sequestration of UBC9 in the cytoplasm, leading to inhibition of STAT1 sumoylation. Hence, NMI functions as a switch for STAT1 activation/inactivation cycles by modulating an IFNγ‐induced desensitization mechanism. NMI facilitates UBC9 nucleus‐to‐cytoplasm translocation in response to IFNγ, thereby inhibiting STAT1 sumoylation, leading to enhanced STAT1 phosphorylation and consequent increased cellular signaling responses to IFNγ. NMI functions as a switch for STAT1 activation/inactivation cycles.