Human Cytomegalovirus UL23 Attenuates Signal Transducer and Activator of Transcription 1 Phosphorylation and Type I Interferon Response

Feng, Linyuan; Li, Wanwei; Wu, Xiumei; Li, Xiaotian; Yang, Xiaoping; Ran, Yanhong; Wu, Jianguo; Li, Hongjian

doi:10.3389/fmicb.2021.692515

Cited by 12 publications

(8 citation statements)

References 57 publications

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“…We have demonstrated that pA104R inhibited ISGF3-mediated ISRE luciferase signaling (Figure 2A), suggesting that pA104R is a suppressor of IFN signaling that likely targets ISGF3 itself or a related downstream process. Previous studies have shown that many viral proteins can subvert the IFN-I signaling pathway by targeting IRF9 or STATs to reduce phosphorylation or stimulate degradation (Palosaari et al, 2003;Fanunza et al, 2021;Feng et al, 2021). Further studies revealed that although pA104R did not interact with any component of ISGF3 (Figure 3), it still attenuated the phosphorylation of STAT1 (Figure 2B).…”

Section: Discussionmentioning

confidence: 87%

African swine fever virus pA104R protein acts as a suppressor of type I interferon signaling

Chen

Guo

et al. 2023

Front. Microbiol.

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This study evaluates the role of the late viral protein, pA104R, in African swine fever virus immunosuppression. ASFV-encoded pA104R is a putative histone-like protein that is highly conserved throughout different virulent and non-virulent isolates. Previous studies have demonstrated that pA104R plays a vital role in the ASFV replication cycle and is a potential target for antiviral therapy. Here, we demonstrated that pA104R is a potent antagonist of type I interferon signaling. IFN-stimulated response element activity and subsequent transcription of co-transfected and endogenous interferon-stimulated genes were attenuated by pA104R treatment in HEK-293 T cells. Immunoprecipitation assay and reciprocal pull-down showed that pA104R does not interact directly with STAT1, STAT2, or IRF9. However, pA104R could inhibit IFN signaling by attenuating STAT1 phosphorylation, and we identified the critical amino acid residues (R/H69,72 and K/R92,94,97) involved through the targeted mutation functional assays. Although pA104R is a histone-like protein localized to the nucleus, it did not inhibit IFN signaling through its DNA-binding capacity. In addition, activation of the ISRE promoter by IRF9-Stat2(TA), a STAT1-independent pathway, was inhibited by pA104R. Further results revealed that both the transcriptional activation and recruitment of transcriptional stimulators by interferon-stimulated gene factor 3 were not impaired. Although we failed to determine a mechanism for pA104R-mediated IFN signaling inhibition other than attenuating the phosphorylation of STAT1, these results might imply a possible involvement of epigenetic modification by ASFV pA104R. Taken together, these findings support that pA104R is an antagonist of type I interferon signaling, which may interfere with multiple signaling pathways.

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Section: Discussionmentioning

confidence: 87%

African swine fever virus pA104R protein acts as a suppressor of type I interferon signaling

Chen

Guo

et al. 2023

Front. Microbiol.

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“…Their translation happens in three post‐infection stages: IE, early (E), and late (L), which interact with physiological cellular activities 3 . CMV‐infected cell activates the STAT1/2/3 axis through many mechanisms such as US28, 161 IL6, Platelet‐derivedgrowth factor receptor (PDGFR), 158 IFN‐ß, 162 UL23, 163 IL10 164‐167 (Figure 5).…”

Section: Data Extractionmentioning

confidence: 99%

Association between cytomegalovirus infection and neurological disorders: A systematic review

Sanami,

Shamsabadi,

Dayhimi

et al. 2024

Reviews in Medical Virology

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Cytomegalovirus (CMV) belongs to the Herpesviridae family and is also known as human herpesvirus type 5. It is a common virus that usually doesn't cause any symptoms in healthy individuals. However, once infected, the virus remains in the host's body for life and can reactivate when the host's immune system weakens. This virus has been linked to several neurological disorders, including Alzheimer's disease, Parkinson's disease, Autism spectrum disorder, Huntington's disease (HD), ataxia, Bell's palsy (BP), and brain tumours, which can cause a wide range of symptoms and challenges for those affected. CMV may influence inflammation, contribute to brain tissue damage, and elevate the risk of moderate‐to‐severe dementia. Multiple studies suggest a potential association between CMV and ataxia in various conditions, including Guillain‐Barré syndrome, chronic inflammatory demyelinating polyneuropathy, acute cerebellitis, etc. On the other hand, the evidence regarding CMV involvement in BP is conflicting, and also early indications of a link between CMV and HD were challenged by subsequent research disproving CMV's presence. This systematic review aims to comprehensively investigate any link between the pathogenesis of CMV and its potential role in neurological disorders and follows the preferred reporting items for systematic review and meta‐analysis checklist. Despite significant research into the potential links between CMV infection and various neurological disorders, the direct cause‐effect relationship is not fully understood and several gaps in knowledge persist. Therefore, continued research is necessary to gain a better understanding of the role of CMV in neurological disorders and potential treatment avenues.

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“…Ul23, a tegument protein of HCMV, can significantly decrease the expression of ISGs and the activity of the promoter of the response elements of ISGs during HCMV infection. UL23 is a key factor in the negative regulation of type I IFN-mediated immune responses ( 71 ). HCMV inhibits the cGAS-STING-TBK1 pathway and decreases IFN-β mRNA accumulation via its latent associated protein UL138 ( 72 ).…”

Section: Cgas-sting Pathway and Hhv Infectionsmentioning

confidence: 99%

The battle between the innate immune cGAS-STING signaling pathway and human herpesvirus infection

et al. 2023

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The incidence of human herpesvirus (HHVs) is gradually increasing and has affected a wide range of population. HHVs can result in serious consequences such as tumors, neonatal malformations, sexually transmitted diseases, as well as pose an immense threat to the human health. The cGAS-STING pathway is one of the innate immune pattern-recognition receptors discovered recently. This article discusses the role of the cGAS-STING pathway in human diseases, especially in human herpesvirus infections, as well as highlights how these viruses act on this pathway to evade the host immunity. Moreover, the author provides a comprehensive overview of modulators of the cGAS-STING pathway. By focusing on the small molecule compounds based on the cGAS-STING pathway, novel targets and concepts have been proposed for the development of antiviral drugs and vaccines, while also providing a reference for the investigation of disease models related to the cGAS-STING pathway. HHV is a double-stranded DNA virus that can trigger the activation of intracellular DNA sensor cGAS, after which the host cells initiate a cascade of reactions that culminate in the secretion of type I interferon to restrict the viral replication. Meanwhile, the viral protein can interact with various molecules in the cGAS-STING pathway. Viruses can evade immune surveillance and maintain their replication by inhibiting the enzyme activity of cGAS and reducing the phosphorylation levels of STING, TBK1 and IRF3 and suppressing the interferon gene activation. Activators and inhibitors of the cGAS-STING pathway have yielded numerous promising research findings in vitro and in vivo pertaining to cGAS/STING-related disease models. However, there remains a dearth of small molecule modulators that have been successfully translated into clinical applications, which serves as a hurdle to be overcome in the future.

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Human Cytomegalovirus UL23 Attenuates Signal Transducer and Activator of Transcription 1 Phosphorylation and Type I Interferon Response

Cited by 12 publications

References 57 publications

African swine fever virus pA104R protein acts as a suppressor of type I interferon signaling

African swine fever virus pA104R protein acts as a suppressor of type I interferon signaling

Association between cytomegalovirus infection and neurological disorders: A systematic review

The battle between the innate immune cGAS-STING signaling pathway and human herpesvirus infection

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