title: Hepatitis C Virus NS4B Can Suppress STING Accumulation To Evade Innate Immune Responses.
abstract: The cyclic dinucleotide 2',3'-cGAMP can bind the adaptor protein STING (stimulator of interferon [IFN] genes) to activate the production of type I IFNs and proinflammatory cytokines. We found that cGAMP added to the culture medium could suppress the replication of the hepatitis C virus (HCV) genotype 1b strain Con1 subgenomic replicon in human hepatoma cells. Knockdown of STING expression diminished the inhibitory effect on replicon replication, while overexpression of STING enhanced the inhibitory effects of cGAMP. The addition of cGAMP into 1b/Con1 replicon cells significantly increased the expression of type I IFNs and antiviral interferon-stimulated genes. Unexpectedly, replication of the genotype 2a JFH1 replicon and infectious JFH1 virus was less sensitive to the inhibitory effect of cGAMP than was that of 1b/Con1 replicon. Using chimeric replicons, 2a NS4B was identified to confer resistance to cGAMP. Transient expression of 2a NS4B resulted in a pronounced inhibitory effect on STING-mediated beta IFN (IFN-β) reporter activation compared to that of 1b NS4B. 2a NS4B was found to suppress STING accumulation in a dose-dependent manner. The predicted transmembrane domain of 2a NS4B was required to inhibit STING accumulation. These results demonstrate a novel genotype-specific inhibition of the STING-mediated host antiviral immune response.
  
  
  OBJECTIVE
  The cyclic dinucleotide cGAMP was found to potently inhibit the replication of HCV genotype 1b Con1 replicon but was less effective for the 2a/JFH1 replicon and infectious JFH1 virus. The predicted transmembrane domain in 2a NS4B was shown to be responsible for the decreased sensitivity to cGAMP. The N terminus of NS4B has been reported to suppress STING-mediated signaling by disrupting the interaction of STING and TBK1 and/or MAVS. We show that 2a/JFH1 NS4B has an additional mechanism to evade STING signaling through suppressing STING accumulation.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA gyi@indiana.edu.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Yi
authors.affiliation: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
authors.forename: Yahong
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Han
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Kouacou V
authors.initials: KV
authors.lastname: Konan
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
authors.forename: Pingwei
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
authors.forename: C Cheng
authors.initials: CC
authors.lastname: Kao
mesh_terms: D045744:Cell Line, Tumor; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D000099197:STING Protein
chemical_list: D008565:Membrane Proteins; D017361:Viral Nonstructural Proteins; C080107:NS4B protein, flavivirus; C532857:STING1 protein, human; D000099197:STING Protein