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Title: 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. - Highlights: • CCCP inhibits IFN-β production induced by various types of the STING pathway activators. • CCCP suppresses the phosphorylation of STING, TBK1, and IRF3 via disrupting the association of STING and TBK1. • The mitochondria fission mediator DRP1 is essential for CCCP-induced suppression of the STING pathway.

Authors:
;  [1];  [2];  [1]
  1. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141 (Korea, Republic of)
  2. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 (United States)
Publication Date:
OSTI Identifier:
22719133
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 493; Journal Issue: 1; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETIC ACID; AMP; CARBONYLS; CYANIDES; DNA; GENES; INHIBITION; INTERFERON; KNOCK-OUT REACTIONS; MEMBRANES; MITOCHONDRIA; MOLECULES; NEOPLASMS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; RECEPTORS; TRANSLOCATION; VIRUSES

Citation Formats

Kwon, Dohyeong, Park, Eunbyeol, Sesaki, Hiromi, and Kang, Suk-Jo. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) suppresses STING-mediated DNA sensing pathway through inducing mitochondrial fission. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2017.08.121.
Kwon, Dohyeong, Park, Eunbyeol, Sesaki, Hiromi, & Kang, Suk-Jo. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) suppresses STING-mediated DNA sensing pathway through inducing mitochondrial fission. United States. doi:10.1016/J.BBRC.2017.08.121.
Kwon, Dohyeong, Park, Eunbyeol, Sesaki, Hiromi, and Kang, Suk-Jo. Sat . "Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) suppresses STING-mediated DNA sensing pathway through inducing mitochondrial fission". United States. doi:10.1016/J.BBRC.2017.08.121.
@article{osti_22719133,
title = {Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) suppresses STING-mediated DNA sensing pathway through inducing mitochondrial fission},
author = {Kwon, Dohyeong and Park, Eunbyeol and Sesaki, Hiromi and Kang, Suk-Jo},
abstractNote = {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. - Highlights: • CCCP inhibits IFN-β production induced by various types of the STING pathway activators. • CCCP suppresses the phosphorylation of STING, TBK1, and IRF3 via disrupting the association of STING and TBK1. • The mitochondria fission mediator DRP1 is essential for CCCP-induced suppression of the STING pathway.},
doi = {10.1016/J.BBRC.2017.08.121},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 493,
place = {United States},
year = {2017},
month = {11}
}