Abstract STING and cGAS initiate innate immune responses (IIR) by recognizing cytoplasmic pathogen dsDNA and activating signaling cascades from the ER; however, another less investigated pool of STING resides in the nuclear envelope. We find that STING in the inner nuclear membrane increases mobility and changes localization upon IIR activation both from dsDNA and poly(I:C) stimuli. We next identified nuclear partners of STING from isolated nuclear envelopes. These include several known nuclear membrane proteins, bromodomain and epigenetic enzymes, and RNA- or DNA-binding proteins. Strikingly, 17 of these DNA and RNA-binding STING partners are known to bind direct partners of the IRF3/7 transcription factors that are central drivers of IIR. We find that several of these STING partners —SYNCRIP, Men1, Ddx5, snRNP70, RPS27a, Aatf— can contribute to IIR activation and SYNCRIP can moreover protect against influenza A virus infection. These data suggest that the many roles identified for STING likely reflect its interactions with multiple RNA and DNA-binding proteins that also function in IIR.

STING Nuclear Partners Contribute to Innate Immune Signalling Responses