The Experts below are selected from a list of 178188 Experts worldwide ranked by ideXlab platform
Genhong Cheng - One of the best experts on this subject based on the ideXlab platform.
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TANK-binding Kinase 1 Attenuates PTAP-Dependent Retroviral Budding through Targeting Endosomal Sorting Complex Required for Transport-I
Journal of immunology (Baltimore Md. : 1950), 2011Co-Authors: Xuanming Yang, Genhong Cheng, Guangxia Gao, Hong TangAbstract:Retroviruses need to bud from producer cells to spread infection. To facilitate its budding, some virus hijacks the multivesicular body (MVB) pathway that is normally used to cargo and degrade ubiquitylated cellular proteins, through interaction between the late domain of Gag polyproteins and the components of MVB machinery. In this study, we demonstrated that TANK-binding Kinase 1 (TBK1) directly interacted with VPS37C, a subunit of endosomal sorting complex required for transport-I (ESCRT-I) in the MVB pathway, without affecting the ultrastructure or general function of MVB. Interestingly, overexpression of TBK1 attenuated, whereas short hairpin RNA interference of TBK1 enhanced HIV-1 pseudovirus release from Vero cells in type I IFN (IFN-I)-independent manner. Down-regulation of TBK1 by short hairpin RNA in TZM-bl cells also enhanced live HIV-1 NL4-3 or JR-CSF virus budding without involvement of IFN-I induction. Furthermore, infection of TBK1-deficient mouse embryonic fibroblast cells with a chimeric murine leukemia virus/p6, whose PPPY motif was replaced by PTAP motif of HIV-1, showed that lack of TBK1 significantly enhanced PTAP-dependent, but not PPPY-dependent retrovirus budding. Finally, phosphorylation of VPS37C by TBK1 might regulate the viral budding efficiency, because overexpression of the Kinase-inactive mutant of TBK1 (TBK1-K38A) in Vero cells accelerated HIV-1 pseudovirus budding. Therefore, through tethering to VPS37C of the ESCRT-I complex, TBK1 controlled the speed of PTAP-dependent retroviral budding through phosphorylation of VPS37C, which would serve as a novel mechanism of host cell defense independent of IFN-I signaling.
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TANK-binding Kinase-1 plays an important role during in vitro and in vivo type I IFN responses to DNA virus infections.
Journal of immunology (Baltimore Md. : 1950), 2009Co-Authors: Andrea K. Miyahira, Arash Shahangian, Seungmin Hwang, Ren Sun, Genhong ChengAbstract:TANK-binding Kinase-1 (TBK1) and the inducible IκB Kinase (IKK-i) have recently been shown to activate type I IFN responses elicited by intracellular detection of RNA or DNA from infecting viruses. Detection of viral RNA is mediated by retinoic acid inducible gene-I or melanoma differentiation-associated gene-5 pathways in which TBK1 and IKK-i have been demonstrated to play redundant roles in IFN activation. In this study, we have examined whether such redundancy occurs in the type I IFN response to DNA viral challenges by examining induction of IFNs and IFN-mediated signaling and gene programs in TBK1−/− macrophages. In contrast to the normal IFN responses in TBK1−/− macrophages infected with an RNA virus, IFN responses were severely abrogated during DNA virus infections in TBK1−/− macrophages. Because both TBK1 and IKK-i are expressed in macrophages, our studies suggest that TBK1 and IKK-i differ functionally in DNA virus-mediated IFN responses; however, they are redundant in RNA virus-mediated IFN responses. Confirmatively, reconstitution of TBK1−/−IKK-i−/− fibroblasts revealed that TBK1 rescued IFN responses to transfected B-DNA to a much stronger degree than IKK-i. Finally, we demonstrate the requirement for the TBK1-IFN regulatory factor-3 pathway in host defense against a DNA virus infection in vivo.
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modulation of the interferon antiviral response by the tbk1 ikki adaptor protein tank
Journal of Biological Chemistry, 2007Co-Authors: Beichu Guo, Genhong ChengAbstract:Abstract Induction of type I interferons can be triggered by viral components through Toll-like receptors or intracellular viral receptors such as retinoic acid-inducible gene I. Here, we demonstrate that the TRAF (tumor necrosis factor receptor-associated factor) family member-associated NF-κB activator (TANK) plays an important role in interferon induction through both retinoic acid-inducible gene I- and Toll-like receptor-dependent pathways. TANK forms complexes with both upstream signal mediators, such as Cardif/MAVS/IPS-1/VISA, TRIF (Toll-interleukin-1 receptor domain-containing adaptor inducing interferon-β), and TRAF3 and downstream mediators TANK-binding Kinase 1, inducible IκB Kinase, and interferon regulatory factor 3. In addition, it synergizes with these signaling components in interferon induction. Specific knockdown of TANK results in reduced type I interferon production, increased viral titers, and enhanced cell sensitivity to viral infection. Thus, TANK may be a critical adaptor that regulates the assembly of the TANK-binding Kinase 1-inducible IκB Kinase complex with upstream signaling molecules in multiple antiviral pathways.
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Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK.
The Journal of biological chemistry, 2007Co-Authors: Beichu Guo, Genhong ChengAbstract:Abstract Induction of type I interferons can be triggered by viral components through Toll-like receptors or intracellular viral receptors such as retinoic acid-inducible gene I. Here, we demonstrate that the TRAF (tumor necrosis factor receptor-associated factor) family member-associated NF-κB activator (TANK) plays an important role in interferon induction through both retinoic acid-inducible gene I- and Toll-like receptor-dependent pathways. TANK forms complexes with both upstream signal mediators, such as Cardif/MAVS/IPS-1/VISA, TRIF (Toll-interleukin-1 receptor domain-containing adaptor inducing interferon-β), and TRAF3 and downstream mediators TANK-binding Kinase 1, inducible IκB Kinase, and interferon regulatory factor 3. In addition, it synergizes with these signaling components in interferon induction. Specific knockdown of TANK results in reduced type I interferon production, increased viral titers, and enhanced cell sensitivity to viral infection. Thus, TANK may be a critical adaptor that regulates the assembly of the TANK-binding Kinase 1-inducible IκB Kinase complex with upstream signaling molecules in multiple antiviral pathways.
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Immune Activation of Type I IFNs by Listeria monocytogenes Occurs Independently of TLR4, TLR2, and Receptor Interacting Protein 2 but Involves TANK-binding Kinase 1
Journal of immunology (Baltimore Md. : 1950), 2005Co-Authors: Ryan M. O’connell, Andrea K Perry, Sagar A. Vaidya, Supriya K. Saha, Paul W. Dempsey, Genhong ChengAbstract:Type I IFNs are well established antiviral cytokines that have also been shown to be induced by bacteria. However, the signaling mechanisms regulating the activation of these cytokines during bacterial infections remain poorly defined. We show that although Gram-negative bacteria can activate the type I IFN pathway through TLR4, the intracellular Gram-positive bacterium Listeria monocytogenes (LM) can do so independently of TLR4 and TLR2. Furthermore, experiments using genetic mutants and chemical inhibitors suggest that LM-induced type I IFN activation occurs by an intracellular pathway involving the serine-threonine Kinase TNFR-associated NF-κB Kinase (TANK)-binding Kinase 1 (TBK1). Interestingly, receptor-interacting protein 2, a component of the recently discovered nucleotide-binding oligomerization domain-dependent intracellular detection pathway, was not involved. Taken together, our data describe a novel signal transduction pathway involving TBK1 that is used by LM to activate type I IFNs. Additionally, we provide evidence that both the LM- and TLR-dependent pathways converge at TBK1 to activate type I IFNs, highlighting the central role of this molecule in modulating type I IFNs in host defense and disease.
Zhipeng Yan - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of TANK Binding Kinase 1 by Herpes Simplex Virus 1 Facilitates Productive Infection
Journal of virology, 2011Co-Authors: Huali Jin, Tibor Valyi-nagy, Youjia Cao, Zhipeng YanAbstract:ABSTRACT The γ 1 34.5 protein of herpes simplex viruses (HSV) is essential for viral pathogenesis, where it precludes translational arrest mediated by double-stranded-RNA-dependent protein Kinase (PKR). Paradoxically, inhibition of PKR alone is not sufficient for HSV to exhibit viral virulence. Here we report that γ 1 34.5 inhibits TANK binding Kinase 1 (TBK1) through its amino-terminal sequences, which facilitates viral replication and neuroinvasion. Compared to wild-type virus, the γ 1 34.5 mutant lacking the amino terminus induces stronger antiviral immunity. This parallels a defect of γ 1 34.5 for interacting with TBK1 and reducing phosphorylation of interferon (IFN) regulatory factor 3. This activity is independent of PKR. Although resistant to IFN treatment, the γ 1 34.5 amino-terminal deletion mutant replicates at an intermediate level between replication of wild-type virus and that of the γ 1 34.5 null mutant in TBK1 +/+ cells. However, such impaired viral growth is not observed in TBK1 −/− cells, indicating that the interaction of γ 1 34.5 with TBK1 dictates HSV infection. Upon corneal infection, this mutant replicates transiently but barely invades the trigeminal ganglia or brain, which is a difference from wild-type virus and the γ 1 34.5 null mutant. Therefore, in addition to PKR, γ 1 34.5 negatively regulates TBK1, which contributes viral replication and spread in vivo .
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Dephosphorylation of eIF2α Mediated by the γ134.5 Protein of Herpes Simplex Virus 1 Facilitates Viral Neuroinvasion
Journal of virology, 2009Co-Authors: Dustin Verpooten, Zhipeng Yan, Huali Jin, Tibor Valyi-nagy, Zongdi Feng, Cuizhu Zhang, Youjia CaoAbstract:The γ 1 34.5 protein, a virulence factor of herpes simplex viruses, redirects protein phosphatase 1 to dephosphorylate the α subunit of translation initiation factor 2 (eIF2α). Additionally, it inhibits the induction of antiviral genes by TANK-binding Kinase 1. Nevertheless, its precise role in vivo remains to be established. Here we show that eIF2α dephosphorylation by γ 1 34.5 is crucial for viral neuroinvasion. V 193 E and F 195 L substitutions in γ 1 34.5 abrogate viral replication in the eye and spread to the trigeminal ganglia and brain. Intriguingly, inhibition of antiviral gene induction by γ 1 34.5 is not sufficient to exhibit viral virulence.
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control of tank binding Kinase 1 mediated signaling by the γ134 5 protein of herpes simplex virus 1
Journal of Biological Chemistry, 2009Co-Authors: Dustin Verpooten, Songwang Hou, Zhipeng YanAbstract:TANK-binding Kinase 1 (TBK1) is a key component of Toll-like receptor-dependent and -independent signaling pathways. In response to microbial components, TBK1 activates interferon regulatory factor 3 (IRF3) and cytokine expression. Here we show that TBK1 is a novel target of the gamma(1)34.5 protein, a virulence factor whose expression is regulated in a temporal fashion. Remarkably, the gamma(1)34.5 protein is required to inhibit IRF3 phosphorylation, nuclear translocation, and the induction of antiviral genes in infected cells. When expressed in mammalian cells, the gamma(1)34.5 protein forms complexes with TBK1 and disrupts the interaction of TBK1 and IRF3, which prevents the induction of interferon and interferon-stimulated gene promoters. Down-regulation of TBK1 requires the amino-terminal domain. In addition, unlike wild type virus, a herpes simplex virus mutant lacking gamma(1)34.5 replicates efficiently in TBK1(-/-) cells but not in TBK1(+/+) cells. Addition of exogenous interferon restores the antiviral activity in both TBK1(-/-) and TBK(+/+) cells. Hence, control of TBK1-mediated cell signaling by the gamma(1)34.5 protein contributes to herpes simplex virus infection. These results reveal that TBK1 plays a pivotal role in limiting replication of a DNA virus.
Youjia Cao - One of the best experts on this subject based on the ideXlab platform.
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Productive Infection Herpes Simplex Virus 1 Facilitates Inhibition of TANK Binding Kinase 1 by
2014Co-Authors: Huali Jin, Tibor Valyi-nagy, Youjia CaoAbstract:erpes simplex virus 1 (HSV-1) infects epithelial cells of mu-cosal tissues and establishes latency in the trigeminal ganglia(TG). Upon primary infection or reactivation, viral gene expres-sion, DNA replication, and maturation ensue, which can lead topathologicalconditions,includingocularlesionsandencephalitis(48). Although multiple factors are involved, the
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Inhibition of TANK Binding Kinase 1 by Herpes Simplex Virus 1 Facilitates Productive Infection
Journal of virology, 2011Co-Authors: Huali Jin, Tibor Valyi-nagy, Youjia Cao, Zhipeng YanAbstract:ABSTRACT The γ 1 34.5 protein of herpes simplex viruses (HSV) is essential for viral pathogenesis, where it precludes translational arrest mediated by double-stranded-RNA-dependent protein Kinase (PKR). Paradoxically, inhibition of PKR alone is not sufficient for HSV to exhibit viral virulence. Here we report that γ 1 34.5 inhibits TANK binding Kinase 1 (TBK1) through its amino-terminal sequences, which facilitates viral replication and neuroinvasion. Compared to wild-type virus, the γ 1 34.5 mutant lacking the amino terminus induces stronger antiviral immunity. This parallels a defect of γ 1 34.5 for interacting with TBK1 and reducing phosphorylation of interferon (IFN) regulatory factor 3. This activity is independent of PKR. Although resistant to IFN treatment, the γ 1 34.5 amino-terminal deletion mutant replicates at an intermediate level between replication of wild-type virus and that of the γ 1 34.5 null mutant in TBK1 +/+ cells. However, such impaired viral growth is not observed in TBK1 −/− cells, indicating that the interaction of γ 1 34.5 with TBK1 dictates HSV infection. Upon corneal infection, this mutant replicates transiently but barely invades the trigeminal ganglia or brain, which is a difference from wild-type virus and the γ 1 34.5 null mutant. Therefore, in addition to PKR, γ 1 34.5 negatively regulates TBK1, which contributes viral replication and spread in vivo .
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Dephosphorylation of eIF2α Mediated by the γ134.5 Protein of Herpes Simplex Virus 1 Facilitates Viral Neuroinvasion
Journal of virology, 2009Co-Authors: Dustin Verpooten, Zhipeng Yan, Huali Jin, Tibor Valyi-nagy, Zongdi Feng, Cuizhu Zhang, Youjia CaoAbstract:The γ 1 34.5 protein, a virulence factor of herpes simplex viruses, redirects protein phosphatase 1 to dephosphorylate the α subunit of translation initiation factor 2 (eIF2α). Additionally, it inhibits the induction of antiviral genes by TANK-binding Kinase 1. Nevertheless, its precise role in vivo remains to be established. Here we show that eIF2α dephosphorylation by γ 1 34.5 is crucial for viral neuroinvasion. V 193 E and F 195 L substitutions in γ 1 34.5 abrogate viral replication in the eye and spread to the trigeminal ganglia and brain. Intriguingly, inhibition of antiviral gene induction by γ 1 34.5 is not sufficient to exhibit viral virulence.
Huali Jin - One of the best experts on this subject based on the ideXlab platform.
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Productive Infection Herpes Simplex Virus 1 Facilitates Inhibition of TANK Binding Kinase 1 by
2014Co-Authors: Huali Jin, Tibor Valyi-nagy, Youjia CaoAbstract:erpes simplex virus 1 (HSV-1) infects epithelial cells of mu-cosal tissues and establishes latency in the trigeminal ganglia(TG). Upon primary infection or reactivation, viral gene expres-sion, DNA replication, and maturation ensue, which can lead topathologicalconditions,includingocularlesionsandencephalitis(48). Although multiple factors are involved, the
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Inhibition of TANK Binding Kinase 1 by Herpes Simplex Virus 1 Facilitates Productive Infection
Journal of virology, 2011Co-Authors: Huali Jin, Tibor Valyi-nagy, Youjia Cao, Zhipeng YanAbstract:ABSTRACT The γ 1 34.5 protein of herpes simplex viruses (HSV) is essential for viral pathogenesis, where it precludes translational arrest mediated by double-stranded-RNA-dependent protein Kinase (PKR). Paradoxically, inhibition of PKR alone is not sufficient for HSV to exhibit viral virulence. Here we report that γ 1 34.5 inhibits TANK binding Kinase 1 (TBK1) through its amino-terminal sequences, which facilitates viral replication and neuroinvasion. Compared to wild-type virus, the γ 1 34.5 mutant lacking the amino terminus induces stronger antiviral immunity. This parallels a defect of γ 1 34.5 for interacting with TBK1 and reducing phosphorylation of interferon (IFN) regulatory factor 3. This activity is independent of PKR. Although resistant to IFN treatment, the γ 1 34.5 amino-terminal deletion mutant replicates at an intermediate level between replication of wild-type virus and that of the γ 1 34.5 null mutant in TBK1 +/+ cells. However, such impaired viral growth is not observed in TBK1 −/− cells, indicating that the interaction of γ 1 34.5 with TBK1 dictates HSV infection. Upon corneal infection, this mutant replicates transiently but barely invades the trigeminal ganglia or brain, which is a difference from wild-type virus and the γ 1 34.5 null mutant. Therefore, in addition to PKR, γ 1 34.5 negatively regulates TBK1, which contributes viral replication and spread in vivo .
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Dephosphorylation of eIF2α Mediated by the γ134.5 Protein of Herpes Simplex Virus 1 Facilitates Viral Neuroinvasion
Journal of virology, 2009Co-Authors: Dustin Verpooten, Zhipeng Yan, Huali Jin, Tibor Valyi-nagy, Zongdi Feng, Cuizhu Zhang, Youjia CaoAbstract:The γ 1 34.5 protein, a virulence factor of herpes simplex viruses, redirects protein phosphatase 1 to dephosphorylate the α subunit of translation initiation factor 2 (eIF2α). Additionally, it inhibits the induction of antiviral genes by TANK-binding Kinase 1. Nevertheless, its precise role in vivo remains to be established. Here we show that eIF2α dephosphorylation by γ 1 34.5 is crucial for viral neuroinvasion. V 193 E and F 195 L substitutions in γ 1 34.5 abrogate viral replication in the eye and spread to the trigeminal ganglia and brain. Intriguingly, inhibition of antiviral gene induction by γ 1 34.5 is not sufficient to exhibit viral virulence.
Wei Zhao - One of the best experts on this subject based on the ideXlab platform.
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TANK-binding Kinase 1 as a novel therapeutic target for viral diseases.
Expert opinion on therapeutic targets, 2019Co-Authors: Chunyuan Zhao, Wei ZhaoAbstract:Introduction: TANK-binding Kinase 1 (TBK1) is vital for the induction of antiviral innate immune responses. Both RNA and DNA viral infection induces TBK1 activation, triggers phosphorylation of int...
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Ubiquitin-Specific Protease 2b Negatively Regulates IFN-β Production and Antiviral Activity by Targeting TANK-binding Kinase 1
Journal of immunology (Baltimore Md. : 1950), 2014Co-Authors: Lei Zhang, Wei Zhao, Xueying Zhao, Meng Zhang, Chengjiang GaoAbstract:TANK-binding Kinase 1 (TBK1) is essential for IFN regulatory factor 3 activation and IFN-β production downstream of various innate receptors. However, how TBK1 activation is terminated is not well defined. In this study, we identified ubiquitin-specific protease (USP) 2b as a new negative regulator for TBK1 activation. Overexpression of USP2b inhibited retinoic acid-inducible gene-I-mediated IFN-β signaling; in contrast, knockdown of USP2b expression by small interfering RNA enhanced retinoic acid-inducible gene-I-mediated IFN-β signaling. Coimmunoprecipitation experiments demonstrated that USP2b interacted with TBK1. As a deubiquitinating enzyme, USP2b was demonstrated to cleave K63-linked polyubiquitin chains from TBK1 to inhibit TBK1 Kinase activity. Consistent with the inhibitory roles of USP2b on TBK1 activation, knockdown of USP2b significantly inhibited the replication of vesicular stomatitis virus, whereas overexpression of USP2b resulted in enhanced replication of vesicular stomatitis virus. Therefore, our findings demonstrated that USP2b deubiquitinates K63-linked polyubiquitin chains from TBK1 to terminate TBK1 activation and negatively regulate IFN-β signaling and antiviral immune response.
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Lithium Attenuates IFN-β Production and Antiviral Response via Inhibition of TANK-binding Kinase 1 Kinase Activity
Journal of immunology (Baltimore Md. : 1950), 2013Co-Authors: Lijuan Wang, Wei Zhao, Lei Zhang, Xueying Zhao, Meng Zhang, Chengjiang GaoAbstract:Lithium salt is a widely used glycogen synthase Kinase-3β inhibitor and effective drug for the treatment of psychiatric diseases. However, the effects of lithium in innate immune responses, especially in cellular antiviral responses, are unknown. In this study, we show that lithium chloride attenuates LPS-, polyinosinic-polycytidylic acid–, and Sendai virus–induced IFN-β production and IFN regulatory factor 3 activation in macrophages in a glycogen synthase Kinase-3β–independent manner. The ability of the lithium to inhibit IFN-β production was confirmed in vivo, as mice treated with lithium chloride exhibited decreased levels of IFN-β upon Sendai virus infection. In vitro Kinase assay demonstrates that lithium suppresses TANK-binding Kinase 1 Kinase activity. Consistently, lithium significantly enhanced the replication of vesicular stomatitis virus in vitro and in vivo. Severe infiltration of monocytes and tissue damage were observed in the lungs of control mice, compared with lithium-treated mice after virus infection. Our findings suggest lithium as an inhibitor of TANK-binding Kinase 1 and potential target for the intervention of diseases with uncontrolled IFN-β production. Furthermore, lithium attenuates host defense to virus infection and may cause severely adverse effects in clinical applications.
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Negative regulation of TBK1-mediated antiviral immunity.
FEBS letters, 2013Co-Authors: Wei ZhaoAbstract:TANK-binding Kinase 1 (TBK1) plays pivotal roles in antiviral innate immunity. TBK1 mediates the activation of interferon regulatory factor (IRF) 3, leading to the induction of type I IFNs (IFN-α/β) following viral infections. TBK1 must be tightly regulated to effectively control viral infections and maintain immune homeostasis. TBK1 activity can be regulated in a variety of ways, such as phosphorylation, ubiquitination, Kinase activity modulation and prevention of functional TBK1-containing complexes formation. Furthermore, multiple viruses have evolved elaborate strategies to circumvent IFN responses by targeting TBK1. Here we provide an overview of TBK1 in antiviral immunity and recent developments on the regulation of TBK1 activity.
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TRAF-interacting protein (TRIP) negatively regulates IFN-β production and antiviral response by promoting proteasomal degradation of TANK-binding Kinase 1
The Journal of experimental medicine, 2012Co-Authors: Meng Zhang, Wei Zhao, Lijuan Wang, Xueying Zhao, Kai Zhao, Hong Meng, Chengjiang GaoAbstract:TANK-binding Kinase 1 (TBK1) plays an essential role in Toll-like receptor (TLR)– and retinoic acid–inducible gene I (RIG-I)–mediated induction of type I interferon (IFN; IFN-α/β) and host antiviral responses. How TBK1 activity is negatively regulated remains largely unknown. We report that TNF receptor-associated factor (TRAF)–interacting protein (TRIP) promotes proteasomal degradation of TBK1 and inhibits TLR3/4- and RIG-I–induced IFN-β signaling. TRIP knockdown resulted in augmented activation of IFN regulatory factor 3 (IRF3) and enhanced expression of IFN-β in TLR3/4- and RIG-I–activated primary peritoneal macrophages, whereas overexpression of TRIP had opposite effects. Consistently, TRIP impaired Sendai virus (SeV) infection–induced IRF3 activation and IFN-β production and promoted vesicular stomatitis virus (VSV) replication. As an E3 ubiquitin ligase, TRIP negatively regulated the cellular levels of TBK1 by directly binding to and promoting K48-linked polyubiquitination of TBK1. Therefore, we identified TRIP as a negative regulator in TLR3/4- and RIG-I–triggered antiviral responses and suggested TRIP as a potential target for the intervention of diseases with uncontrolled IFN-β production.
