SAM68 directs STING signalling to apoptosis in macrophages

Abstract DNA is a danger signal and is sensed by cGAS to engage signaling through STING for activation of innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 and TBK1 but acts independently of gene transcription. By intersecting four mass spectrometry datasets we identified SAM68 to be important for induction of apoptosis downstream of STING activation. SAM68 was essential for full activation of apoptosis but was not required for STING-mediated activation of IFN expression or activation of NF-kB. Mechanistic studies revealed that protein trafficking was necessary and involved SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a novel STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.