Besides its important role in innate immune response to
DNA virus infection, the regulatory function of
STING in autoimmunity and
cancer is emerging. Recently, multiple mechanisms regulating the activity of the
STING pathway have been revealed. Previous study showed that
carbonyl cyanide 3-chlorophenylhydrazone (
CCCP), the protonophore, inhibited
STING-mediated IFN-β production via disrupting mitochondrial membrane potential (
MMP). However, how
MMP dissipation leads to the suppression of the
STING pathway remains unknown. Here, we show that
CCCP inhibits activation of
STING and its downstream signaling molecules, TBK1 and IRF3, but not
STING translocation to the perinuclear region. We found that
CCCP impairs the interaction between
STING and TBK1 and concomitantly triggers mitochondria fission. Importantly, the knockout of the crucial mitochondria fission regulator Drp1 restored the
STING activity, indicating that
CCCP down-modulates the
STING pathway through DRP1-mediated mitochondria fragmentation. Our findings highlight the coupling of the
STING signaling platform to mitochondria dynamics.