Stimulator of IFN genes-mediated DNA-sensing pathway is suppressed by NLRP3 agonists and regulated by mitofusin 1 and TBC1D15, mitochondria dynamics mediators

Abstract

The stimulator of IFN genes (STING)-mediated DNA-sensing pathway plays an important role in the innate immune response to pathogen infection, autoimmunity, and cancer; however, its regulatory mechanism has not been fully elucidated, and we do not yet know whether the STING pathway is counter-regulated by other innate immune pathways. Here, we show that the NLRP3-activating agonists, ATP and nigericin, prevent STING pathway activation in association with mitochondrial fragmentation; however, the suppression of the STING pathway and mitochondria fission were not dependent on NLRP3 or potassium efflux. Although nigericin-induced mitochondria fission was rescued by knockdown of either dynamin-related protein 1 or TBC1 domain family member 15 (TBC1D15), which are two distinct mitochondria fission regulators, only TBC1D15 restored the activity of the STING pathway, which indicates that inflammasome-activating signals curtail STING pathway activation via TBC1D15. Finally, we found that deficiency of mitofusin (MFN) 1, a mediator of mitochondrial fusion, inhibited STING pathway activation, which leads to a decrease in the induction of IFN-β and its inducible gene, ISG56, in conjunction with diminished activation of the signaling molecules, TANK-binding kinase 1 and IFN regulatory factor 3, that are downstream of STING. These results highlight the crucial role of MFN1 in maintaining the competency of the STING pathway. Collectively, our findings reveal that mitochondrial dynamics regulators modulate the activation of the STING signaling pathway.—Kwon, D., Park, E., Kang, S.-J. Stimulator of IFN genes–mediated DNA-sensing pathway is suppressed by NLRP3 agonists and regulated by mitofusin 1 and TBC1D15, mitochondria dynamics mediators.