Human Cytomegalovirus Protein UL31 Inhibits DNA Sensing of cGAS to Mediate Immune Evasion

Huang, Zhe-Fu; Zou, Hong-Mei; Liao, Bo-Wei; Zhang, Hongyan; Yang, Yan; Fu, Yu-Zhi; Wang, Suyun; Luo, Min‐Hua; Wang, Yan-Yi

doi:10.1016/j.chom.2018.05.007

Cited by 94 publications

(91 citation statements)

References 56 publications

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“…To successfully infect and persist in the host, viruses must possess multiple strategies to subvert host immune responses (12)(13)(14). A number of viral proteins that inhibit IFN-I production through modulation of the cGAS-STING DNA-sensing pathway have been identified, including HSV-1 UL41 (15), VP22 (16), VP24 (18), ICP27 (19), UL24 (20), and VP11/12 (35), as well as viral proteins encoded by KSHV (9), human cytomegalovirus (17,36), and murine gammaherpesvirus 68 (37). Nevertheless, to date, the strategies used by chicken DNA viruses to hinder the DNA-sensing pathway in host cells remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation

Gao

Zhang

et al. 2019

J Virol

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The type I interferon (IFN) response is the first line of host innate immune defense against viral infection; however, viruses have developed multiple strategies to antagonize host IFN responses for efficient infection and replication.Here, we report that Marek's disease virus (MDV), an oncogenic herpesvirus, encodes VP23 protein as a novel immune modulator to block the beta interferon (IFN-␤) activation induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) in chicken fibroblasts and macrophages. VP23 overexpression markedly reduces viral DNA-triggered IFN-␤ production and promotes viral replication, while knockdown of VP23 during MDV infection enhances the IFN-␤ response and suppresses viral replication. VP23 selectively inhibits IFN regulatory factor 7 (IRF7) but not nuclear factor B (NF-B) activation. Furthermore, we found that VP23 interacts with IRF7 and blocks its binding to TANK-binding kinase 1 (TBK1), thereby inhibiting IRF7 phosphorylation and nuclear translocation, resulting in reduced IFN-␤ production. These findings expand our knowledge of DNA sensing in chickens and reveal a mechanism through which MDV antagonizes the host IFN response. IMPORTANCE Despite widespread vaccination, Marek's disease (MD) continues to pose major challenges for the poultry industry worldwide. MDV causes immunosuppression and deadly lymphomas in chickens, suggesting that this virus has developed a successful immune evasion strategy. However, little is known regarding the initiation and modulation of the host innate immune response during MDV infection. This study demonstrates that the cGAS-STING DNA-sensing pathway is critical for the induction of the IFN-␤ response against MDV infection in chicken fibroblasts and macrophages. An MDV protein, VP23, was found to efficiently inhibit the cGAS-STING pathway. VP23 selectively inhibits IRF7 but not NF-B activation. VP23 interacts with IRF7 and blocks its binding to TBK1, thereby suppressing IRF7 activation and resulting in inhibition of the DNA-sensing pathway. These findings expand our knowledge of DNA sensing in chickens and reveal a mechanism through which MDV antagonizes the host IFN response.

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Section: Discussionmentioning

confidence: 99%

Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation

Gao

Zhang

et al. 2019

J Virol

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“…cGAS and STING are both undergoing positive selection 53,54 , which predicts specific virally-encoded antagonists of these key proteins. Indeed, cGAS-STING pathway antagonists encoded by diverse viruses including HSV-1 [55][56][57] , adenovirus 58 , human papillomavirus (HPV) 58 , human cytomegalovirus (CMV) 59 , Kaposi's sarcoma herpes virus (KSHV) 60,61,62 , and hepatitis B (HBV) 63 have already been discovered, and it is likely that all DNA viruses encode at least one cGAS/STING antagonist. Additionally, many RNA viruses encode antagonists of the cGAS-STING pathway, likely in order to avoid cGAS-mediated recognition of mitochondrial DNA that is released after infection induces mitochondrial stress 64 .…”

Section: Viral Antagonism Of Dna Sensingmentioning

confidence: 99%

Human DNA-PK activates a STING-independent DNA sensing pathway

et al. 2020

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Human DNA-PK activates a STING-independent DNA sensing pathway Recognition of foreign nucleic acids is critical for antiviral defense. Detection of DNA is mediated by the cGAS-STING pathway, which activates a potent type I interferon response. This pathway is broadly required for antiviral defense across cell types and species, and its relevance in context of infection, cancer, and autoimmunity has been thoroughly established. However, we have discovered an additional, STING-independent DNA sensing pathway (SIDSP) in human cells. Using STING KO human cell lines, we find that the induction of interferon is indeed abrogated at early timepoints, but surprisingly, at later timepoints, we observe a robust DNAinduced interferon response. Here we identify DNA-PK as the sensor for the SIDSP and demonstrate that its kinase activity is required for the antiviral response. We show that a heat shock protein HSPA8/HSC70 is phosphorylated after DNA stimulation and acts as a marker for the SIDSP. Finally, we explore how DNA viruses antagonize both the cGAS-STING pathway and the SIDSP. Our work highlights the importance of nucleic acid sensing for both host and virus and has implications for modulating DNA sensing in order to improve therapies for cancer or autoimmunity.

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“…Various HCMV proteins target many steps of innate and adaptive immune responses. For example, UL82 (8), UL31 (9), US9 (10), UL23 (11), UL38 (12), UL83 (13,14), TRS1 (15), and UL26 (16) modulate innate and adaptive immune responses through distinct mechanisms.…”

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confidence: 99%

Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

Zou

et al. 2019

J Virol

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Innate immunity is the first line of host defense against viral invasion. The induction of type I interferons (IFNs) and inflammatory cytokines is essential to host antiviral immune responses, which are also key targets of viral immune evasion. Human cytomegalovirus (HCMV) can establish long-term latent infections, in which immune evasion is a pivotal step. In this study, we identified HCMV protein UL44, a DNA polymerase processivity factor, as an inhibitor of the interferon regulatory factor 3 (IRF3)-and NF-B-dependent antiviral response. Ectopic expression of UL44 inhibited HCMV-triggered induction of downstream effector genes and enhanced viral replication. Conversely, knockdown of UL44 potentiated HCMV-triggered induction of downstream antiviral genes. UL44 interacted with IRF3 and p65, and it inhibited the binding of IRF3 and NF-B to the promoters of their downstream antiviral genes. These findings reveal an important mechanism of immune evasion by HCMV at the transcriptional level. IMPORTANCE Induction of type I IFNs and inflammatory cytokines plays pivotal roles in host antiviral innate immune responses. Viruses have evolved various mechanisms to interfere with these processes. HCMV causes severe ailments in immunodeficient populations and is a major cause of birth defects. It has been shown that HCMV antagonizes host innate immune defenses, which is important for establishing immune evasion and latent infection. In this study, we identified the HCMV DNA polymerase subunit UL44 as a suppressor of antiviral innate immune responses. Overexpression of UL44 impaired HCMV-triggered induction of type I IFNs and other antiviral genes and thus potentiated viral replication, whereas UL44 deficiency showed opposite effects. Mechanistic studies indicated that UL44 acts by inhibiting the binding of IRF3 and NF-B to the promoters of downstream antiviral genes. These findings defined an important mechanism of HCMV immune evasion at the transcriptional level, which may provide a therapeutic target for the treatment of HCMV infection.

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Human Cytomegalovirus Protein UL31 Inhibits DNA Sensing of cGAS to Mediate Immune Evasion

Cited by 94 publications

References 56 publications

Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation

Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation

Human DNA-PK activates a STING-independent DNA sensing pathway

Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

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