The STING-mediated DNA sensing pathway is regulated by mitochondria dynamics and inhibited by NLRP3 agonists
Dohyeong Kwon, Eunbyeol Park, and Suk-Jo Kang* Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea *Corresponding Author
Mitochondrial dynamics are coupled to the metabolic function and as reactive oxygen species (ROS) production of mitochondria, mitophagy, and various cellular signaling. Recently, evidence is emerging that mitochondrial dynamics and ROS play important roles in the regulation of innate immune signaling including MAVS-mediated viral RNA sensing and NLRP3-mediated inflammasome pathway. However, the role of mitochondrial dynamics in the stimulator of interferon genes (STING)-mediated DNA sensing pathway has not been investigated. Here, we show that deficiency of mitofusin 1 (MFN1), an effector molecule for mitochondrial fusion, suppressed the activation of the STING pathway, resulting in the decreased induction of interferon (IFN)-β and its target gene, ISG56, in conjunction with diminished activation of the signaling molecules downstream of STING, TBK1 and IRF3. These results highlight the crucial role of MFN1 for maintaining the competency of the STING pathway. In addition, we show that NLRP3-activating agonists, ATP and nigericin, caused mitochondria fragmentation and inhibited the STING pathway. However, the suppression of the STING pathway and mitochondria fission induced by nigericin was not dependent on NLRP3 inflammasome activation and its key element, potassium efflux, and mediated in a DRP1-independent manner. Collectively, our findings reveal that mitochondrial dynamics regulators modulate the STING signaling pathway activity and that inflammasome-activating signals curtail the activation of the STING pathway at mitochondria.