Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity

Ding, Qiang; Cao, Xuezhi; Lu, Jie; Huang, Bing; Liu, Yong Jun; Kato, Naoya; Shu, Hong; Zhong, Jin

doi:10.1016/j.jhep.2013.03.019

Cited by 155 publications

(158 citation statements)

References 30 publications

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“…Collectively, these data suggested that viral genomes and RNA transcripts of baculovirus and cytosolic DNA-dependent RNA polymerase III may participate in the IPS-1-dependent IFN-␤ production in cells infected with recombinant baculovirus. Recently, it has been shown that HCV infection suppresses not only IPS-1-dependent IFN signaling by NS3/4A but also STING-mediated IFN response by NS4B (78,79). Therefore, suppression of STING by HCV replication may participate in the efficient gene transduction in the HCV replicon cells by baculovirus.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Response Induced by Baculovirus Attenuates Transgene Expression in Mammalian Cells

Ono

Ninomiya

Yamamoto

et al. 2014

J Virol

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Section: Discussionmentioning

confidence: 99%

Innate Immune Response Induced by Baculovirus Attenuates Transgene Expression in Mammalian Cells

Ono

Ninomiya

Yamamoto

et al. 2014

J Virol

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“…Hepatic (Huh7 and Huh7.5.1) cells were cultured in complete Dulbecco modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum, 10 mM HEPES, 2 mM L-glutamine, 100 U of penicillin/ml, and 100 mg of streptomycin/ml (Invitrogen, Carlsbad, CA). PH5CH8 cells were cultured in DMEM/F-12 (Invitrogen) as described previously (22). Primary human hepatocytes were purchased from Research Institute for Liver Diseases (Shanghai, China) and cultured at a density of 10 5 cells/cm 2 on 48-well plates coated with type 1 collagen using serum-free differentiation medium.…”

Section: Methodsmentioning

confidence: 99%

“…4A, CH25H expression level was greatly induced, as well as IFN-␤. We then tested PH5CH8 cells, another hepatic cell line that mounts an efficient innate immune response (22,41). As shown in Fig.…”

Section: Hc Inhibits Hcv Infectionmentioning

confidence: 99%

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

Tang

Tao

et al. 2015

J Virol

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Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the Flaviviridae family, causes chronic liver diseases, including hepatitis, cirrhosis, and cancer. HCV infection is critically dependent on host lipid metabolism, which contributes to all stages of the viral life cycle, including virus entry, replication, assembly, and release. 25-Hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses, and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I·C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in humans but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics. IMPORTANCERecent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here, we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated upon poly(I·C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice showing that ch25h is an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy. H epatitis C virus (HCV), a causative agent of acute and chronic liver diseases, is an enveloped positive-sense single-stranded RNA virus belonging to the family of Flaviviridae. Approximately 170 million people worldwide are infected with HCV. The tremendous progress has been achieved in the therapeutics of chronic hepatitis C thanks to the development of direct antiviral agents (DAAs), but the worldwide application of the...

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“…The protocol for the IFN-␤ luciferase reporter assay was described previously (36)(37)(38). Briefly, Huh7 cells seeded in 48-well plates were transfected with 15 ng of IFN-␤ promoter luciferase reporter plasmid pIFΔ(Ϫ125)lucter, 15 ng of Renilla luciferase-expressing plasmid pRL-Tk (Promega, Madison, WI) used to normalize transfection, and 50 ng of pNS3-4A-WT/M21T or the empty vector control using the Exgen 500 transfection reagent (Fermentas, Hanover, MD) for 36 h, followed by another transfection with 0.3 g of poly(I·C) using the Lipofectamine 2000 transfection reagent (Invitrogen) for additional 16 h. The cell lysates were collected, and luciferase activities were measured using the dual-luciferase reporter assay system (Promega) according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

A Point Mutation in the N-Terminal Amphipathic Helix α ₀ in NS3 Promotes Hepatitis C Virus Assembly by Altering Core Localization to the Endoplasmic Reticulum and Facilitating Virus Budding

Boson

et al. 2017

J Virol

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The assembly of hepatitis C virus (HCV), a complicated process in which many viral and cellular factors are involved, has not been thoroughly deciphered. NS3 is a multifunctional protein that contains an N-terminal amphipathic ␣ helix (designated helix ␣ 0 ), which is crucial for the membrane association and stability of NS3 protein, followed by a serine protease domain and a C-terminal helicase/NTPase domain. NS3 participates in HCV assembly likely through its C-terminal helicase domain, in which all reported adaptive mutations enhancing virion assembly reside. In this study, we determined that the N-terminal helix ␣ 0 of NS3 may contribute to HCV assembly. We identified a single mutation from methionine to threonine at amino acid position 21 (M21T) in helix ␣ 0 , which significantly promoted viral production while having no apparent effect on the membrane association and protease activity of NS3. Subsequent analyses demonstrated that the M21T mutation did not affect HCV genome replication but rather promoted virion assembly. Further study revealed a shift in the subcellular localization of core protein from lipid droplets (LD) to the endoplasmic reticulum (ER). Finally, we showed that the M21T mutation increased the colocalization of core proteins and viral envelope proteins, leading to a more efficient envelopment of viral nucleocapsids. Collectively, the results of our study revealed a new function of NS3 helix ␣ 0 and aid understanding of the role of NS3 in HCV virion morphogenesis.IMPORTANCE HCV NS3 protein possesses the protease activity in its N-terminal domain and the helicase activity in its C-terminal domain. The role of NS3 in virus assembly has been mainly attributed to its helicase domain, because all adaptive mutations enhancing progeny virus production are found to be within this domain. Our study identified, for the first time to our knowledge, an adaptive mutation within the N-terminal helix ␣ 0 domain of NS3 that significantly enhanced virus assembly while having no effect on viral genome replication. The mechanistic studies suggested that this mutation promoted the relocation of core proteins from LD to the ER, leading to a more efficient envelopment of viral nucleocapsids. Our results revealed a possible new function of helix ␣ 0 in the HCV life cycle and provided new clues to understanding the molecular mechanisms for the action of NS3 in HCV assembly.KEYWORDS HCV, NS3, core, helix ␣ 0 , assembly, hepatitis C virus

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Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity

Cited by 155 publications

References 30 publications

Innate Immune Response Induced by Baculovirus Attenuates Transgene Expression in Mammalian Cells

Innate Immune Response Induced by Baculovirus Attenuates Transgene Expression in Mammalian Cells

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

A Point Mutation in the N-Terminal Amphipathic Helix α ₀ in NS3 Promotes Hepatitis C Virus Assembly by Altering Core Localization to the Endoplasmic Reticulum and Facilitating Virus Budding

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Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity

Cited by 155 publications

References 30 publications

Innate Immune Response Induced by Baculovirus Attenuates Transgene Expression in Mammalian Cells

Innate Immune Response Induced by Baculovirus Attenuates Transgene Expression in Mammalian Cells

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

A Point Mutation in the N-Terminal Amphipathic Helix α 0 in NS3 Promotes Hepatitis C Virus Assembly by Altering Core Localization to the Endoplasmic Reticulum and Facilitating Virus Budding

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A Point Mutation in the N-Terminal Amphipathic Helix α ₀ in NS3 Promotes Hepatitis C Virus Assembly by Altering Core Localization to the Endoplasmic Reticulum and Facilitating Virus Budding