Human Cytomegalovirus IE2 86 kDa Protein Induces STING Degradation and Inhibits cGAMP-Mediated IFN-β Induction

Kim, Jung-Eun; Kim, Young-Eui; Stinski, Mark F.; Ahn, Jin-Hyun; Song, Yoon‐Jae

doi:10.3389/fmicb.2017.01854

Cited by 41 publications

(35 citation statements)

References 50 publications

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“…While some herpesviral antagonists target cGAS directly Zhang et al, 2016;Su & Zheng, 2017), others mediate the degradation of STING (Kim et al, 2017) or target downstream signaling pathways (Christensen et al, 2016). While some herpesviral antagonists target cGAS directly Zhang et al, 2016;Su & Zheng, 2017), others mediate the degradation of STING (Kim et al, 2017) or target downstream signaling pathways (Christensen et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…The cGAS-STING signaling pathway plays a pivotal role in the antiviral innate immune response with the number of corresponding viral antagonists rising steadily. While some herpesviral antagonists target cGAS directly Zhang et al, 2016;Su & Zheng, 2017), others mediate the degradation of STING (Kim et al, 2017) or target downstream signaling pathways (Christensen et al, 2016). However, the m152 protein is a clear stand out: It modulates this pathway differentially by antagonizing cGAS-STING-mediated activation of type I IFN signaling, while leaving cGAS-STING-mediated activation of NF-jB signaling intact, and it does so by delaying trafficking of STING from the ER to the Golgi compartment (Fig 9).…”

Section: Discussionmentioning

confidence: 99%

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The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection

et al. 2019

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Cytomegaloviruses (CMVs) are master manipulators of the host immune response. Here, we reveal that the murine CMV (MCMV) protein m152 specifically targets the type I interferon (IFN) response by binding to stimulator of interferon genes (STING), thereby delaying its trafficking to the Golgi compartment from where STING initiates type I IFN signaling. Infection with an MCMV lacking m152 induced elevated type I IFN responses and this leads to reduced viral transcript levels both in vitro and in vivo. This effect is ameliorated in the absence of STING. Interestingly, while m152 inhibits STING‐mediated IRF signaling, it did not affect STING‐mediated NF‐κB signaling. Analysis of how m152 targets STING translocation reveals that STING activates NF‐κB signaling already from the ER prior to its trafficking to the Golgi. Strikingly, this response is important to promote early MCMV replication. Our results show that MCMV has evolved a mechanism to specifically antagonize the STING‐mediated antiviral IFN response, while preserving its pro‐viral NF‐κB response, providing an advantage in the establishment of an infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection

et al. 2019

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“…Similar to degradation of cGAS, DENV and other related flaviviruses proteolytically cleave STING using the viral protease complex NS2B3, blocking induction of signaling [45,46 ]. In addition, the HCMV IE86 protein promotes STING degradation in the proteasome, restricting activation of downstream signaling [47].…”

Section: Pathogens Block Sting Signalosome Assemblymentioning

confidence: 99%

Conserved strategies for pathogen evasion of cGAS–STING immunity

Eaglesham

Kranzusch

2020

Current Opinion in Immunology

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The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway of cytosolic DNA sensing allows mammalian cells to detect and respond to infection with diverse pathogens. Pathogens in turn encode numerous factors that inhibit nearly all steps of cGAS-STING signal transduction. From masking of cytosolic DNA ligands, to posttranslational modification of cGAS and STING, and degradation of the nucleotide second messenger 2 0 3 0 -cGAMP, pathogens have evolved convergent mechanisms to evade cGAS-STING sensing. Here we examine pathogen inhibitors of innate immunity in the context of newly discovered regulatory features controlling cellular cGAS-STING activation. Comparative analysis of these strategies provides insight into mechanisms of action and suggests aspects of cGAS-STING regulation and immune evasion that remain to be discovered.

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“…Moreover, the HCMV immediate early (IE) 86 kDa protein (IE86), negatively affects IFN-β mRNA transcription by preventing NF-κB binding to the IFN-β promoter (Taylor and Bresnahan, 2006). Intriguingly, a recent study by Kim et al (2017) has shown that IE86 downregulates STING protein, suggesting that IE86 may also target STING for proteasomal degradation. Interestingly, STING levels were restored upon treatment with the peptide aldehyde MG132, which prevents the proteolytic activity of the proteasome complex.…”

Section: The Ifn System and Hcmv: A Stormy Relationshipmentioning

confidence: 99%

Tuning the Orchestra: HCMV vs. Innate Immunity

et al. 2020

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Understanding how the innate immune system keeps human cytomegalovirus (HCMV) in check has recently become a critical issue in light of the global clinical burden of HCMV infection in newborns and immunodeficient patients. Innate immunity constitutes the first line of host defense against HCMV as it involves a complex array of cooperating effectors -e.g., inflammatory cytokines, type I interferon (IFN-I), natural killer (NK) cells, professional antigen-presenting cells (APCs) and phagocytes -all capable of disrupting HCMV replication. These factors are known to trigger a highly efficient adaptive immune response, where cellular restriction factors (RFs) play a major gatekeeping role. Unlike other innate immunity components, RFs are constitutively expressed in many cell types, ready to act before pathogen exposure. Nonetheless, the existence of a positive regulatory feedback loop between RFs and IFNs is clear evidence of an intimate cooperation between intrinsic and innate immunity. In the course of virushost coevolution, HCMV has, however, learned how to manipulate the functions of multiple cellular players of the host innate immune response to achieve latency and persistence. Thus, HCMV acts like an orchestra conductor able to piece together and rearrange parts of a musical score (i.e., innate immunity) to obtain the best live performance (i.e., viral fitness). It is therefore unquestionable that innovative therapeutic solutions able to prevent HCMV immune evasion in congenitally infected infants and immunocompromised individuals are urgently needed. Here, we provide an up-to-date review of the mechanisms regulating the interplay between HCMV and innate immunity, focusing on the various strategies of immune escape evolved by this virus to gain a fitness advantage.

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Human Cytomegalovirus IE2 86 kDa Protein Induces STING Degradation and Inhibits cGAMP-Mediated IFN-β Induction

Cited by 41 publications

References 50 publications

The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection

The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection

Conserved strategies for pathogen evasion of cGAS–STING immunity

Tuning the Orchestra: HCMV vs. Innate Immunity

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