title: Identification of a negative feedback loop between cyclic di-GMP-induced levels of IFI16 and p202 cytosolic DNA sensors and STING.
abstract: A host type I IFN response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP (c-di-GMP) by STING (stimulator of IFN genes). Because the STING, an adaptor protein, links the cytosolic detection of DNA by the cytosolic DNA sensors such as the IFN-inducible human IFI16 and murine p202 proteins to the TBK1/IRF3 axis, we investigated whether c-di-GMP-induced signaling could regulate expression of IFI16 and p202 proteins. Here, we report that activation of c-di-GMP-induced signaling in human and murine cells increased steady-state levels of IFI16 and p202 proteins. The increase was c-di-GMP concentration- and time-dependent. Unexpectedly, treatment of cells with type I IFN decreased levels of the adaptor protein STING. Therefore, we investigated whether the IFI16 or p202 protein could regulate the expression of STING and activation of the TBK1/IRF3 axis. We found that constitutive knockdown of IFI16 or p202 expression in cells increased steady-state levels of STING. Additionally, the knockdown of IFI16 resulted in activation of the TBK1/IRF3 axis. Accordingly, increased levels of the IFI16 or p202 protein in cells decreased STING levels. Together, our observations identify a novel negative feedback loop between c-di-GMP-induced levels of IFI16 and p202 cytosolic DNA sensors and the adaptor protein STING.
authors.affiliation: Department of Environmental Health, University of Cincinnati, OH, USA Cincinnati VA Medical Center, Cincinnati, OH, USA.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Panchanathan
authors.affiliation: Department of Environmental Health, University of Cincinnati, OH, USA Cincinnati VA Medical Center, Cincinnati, OH, USA.
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Environmental Health, University of Cincinnati, OH, USA.
authors.forename: Duan
authors.initials: D
authors.lastname: Xin
authors.affiliation: Department of Environmental Health, University of Cincinnati, OH, USA Cincinnati VA Medical Center, Cincinnati, OH, USA Divaker.choubey@uc.edu.
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
mesh_terms: D000818:Animals; D002460:Cell Line; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071857:Tumor Suppressor p53-Binding Protein 1; D000099197:STING Protein
chemical_list: D006152:Cyclic GMP; D004247:DNA; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C489664:Ifi16 protein, mouse; C092537:Ifi202b protein, mouse; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C498301:TP53BP1 protein, human; C076700:IFI16 protein, human; C062025:bis(3',5')-cyclic diguanylic acid
keywords: DNA sensors; IFI16; IFNs; STING; c-di-GMP; p202; second messenger