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Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) suppresses STING-mediated DNA sensing pathway through inducing mitochondrial fission.

Abstract
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.
AuthorsDohyeong Kwon, Eunbyeol Park, Hiromi Sesaki, Suk-Jo Kang
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 493 Issue 1 Pg. 737-743 (11 04 2017) ISSN: 1090-2104 [Electronic] United States
PMID28859978 (Publication Type: Journal Article)
CopyrightCopyright © 2017 Elsevier Inc. All rights reserved.
Chemical References
  • Hydrazones
  • Membrane Proteins
  • STING1 protein, human
  • carbonyl 3-chlorophenylhydrazone
  • DNA
Topics
  • Animals
  • DNA (metabolism)
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Hydrazones (administration & dosage)
  • Membrane Potential, Mitochondrial (drug effects, physiology)
  • Membrane Proteins (metabolism)
  • Mice
  • Mitochondrial Dynamics (drug effects, physiology)
  • RAW 264.7 Cells
  • Signal Transduction (drug effects, physiology)

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