Herpes Simplex Virus 1 Tegument Protein US11 Downmodulates the RLR Signaling Pathway via Direct Interaction with RIG-I and MDA-5

Xing, Junji; Wang, Shuai; Lin, Rongtuan; Mossman, Karen; Zheng, Chunfu

doi:10.1128/jvi.06713-11

Cited by 139 publications

(157 citation statements)

References 97 publications

(114 reference statements)

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“…lated, and both can establish latency in sensory ganglia and recurrently reactivate to cause diseases, but they exhibit substantial differences in latency and reactivation patterns (75). A large number of studies have demonstrated that HSV-1 evolved multiple countermeasures to subvert the production of type I IFNs (67,71,(76)(77)(78)(79)(80). However, apart from the report that HSV-2 virion host shutoff (vhs) protein can suppress IFN-b expression (81), current understanding of HSV-2 immune evasion against the production of type I IFNs is limited.…”

Section: Discussionmentioning

confidence: 99%

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

Zhang

Liu

Wang

et al. 2015

The Journal of Immunology

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HSV-2 is the major cause of genital herpes, and its infection increases the risk of HIV-1 acquisition and transmission. After initial infection, HSV-2 can establish latency within the nervous system and thus maintains lifelong infection in humans. It has been suggested that HSV-2 can inhibit type I IFN signaling, but the underlying mechanism has yet to be determined. In this study, we demonstrate that productive HSV-2 infection suppresses Sendai virus (SeV) or polyinosinic-polycytidylic acid-induced IFN-β production. We further reveal that US1, an immediate-early protein of HSV-2, contributes to such suppression, showing that US1 inhibits IFN-β promoter activity and IFN-β production at both mRNA and protein levels, whereas US1 knockout significantly impairs such capability in the context of HSV-2 infection. US1 directly interacts with DNA binding domain of IRF-3, and such interaction suppresses the association of nuclear IRF-3 with the IRF-3 responsive domain of IFN-β promoter, resulting in the suppression of IFN-β promoter activation. Additional studies demonstrate that the 217–414 aa domain of US1 is critical for the suppression of IFN-β production. Our results indicate that HSV-2 US1 downmodulates IFN-β production by suppressing the association of IRF-3 with the IRF-3 responsive domain of IFN-β promoter. Our findings highlight the significance of HSV-2 US1 in inhibiting IFN-β production and provide insights into the molecular mechanism by which HSV-2 evades the host innate immunity, representing an unconventional strategy exploited by a dsDNA virus to interrupt type I IFN signaling pathway.

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Section: Discussionmentioning

confidence: 99%

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

Zhang

Liu

Wang

et al. 2015

The Journal of Immunology

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“…HEK293T, HFF, and Vero cell lines were obtained from the American Type Culture Collection (Manassas, VA) and cultured in Dulbecco's modified Eagle medium (DMEM; Gibco-BRL) supplemented with 10% fetal bovine serum (FBS) and 100 U/ml of penicillin and streptomycin. The wild-type (WT) HSV-1 F strain was propagated in Vero cells and titrated as described previously (41). The protease inhibitor mixture cocktail was purchased from Thermo Fisher Scientific (MA).…”

Section: Methodsmentioning

confidence: 99%

“…HEK293T cells were cotransfected with reporter plasmids, such as IFN-␤-Luc and internal control plasmid pRL-TK, with or without expression plasmids as indicated, by standard calcium phosphate precipitation (45). At 24 h posttransfection, luciferase assays were performed with a dual-luciferase reporter (DLR) assay kit (Promega, Madison, WI) as described in our previous studies (41,46).…”

Section: Methodsmentioning

confidence: 99%

Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

Zheng

2017

J Virol

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141

106

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Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor capable of detecting microbial DNA and activating the adaptor protein stimulator of interferon genes (STING), leading to interferon (IFN) production and host antiviral responses. Cells exhibited reduced type I IFN production in response to cytosolic DNA in the absence of cGAS. Although the cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especially for DNA viruses, few viral components have been identified to specifically target this signaling pathway. Herpes simplex virus 1 (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. In the present study, we found that HSV-1 tegument protein UL41 was involved in counteracting the cGAS/STING-mediated DNA-sensing pathway. Our results showed that wild-type (WT) HSV-1 infection could inhibit immunostimulatory DNA-induced activation of the IFN signaling pathway compared with the UL41-null mutant virus (R2621), and ectopic expression of UL41 decreased cGAS/STINGmediated IFN-␤ promoter activation and IFN-␤ production. Further study indicated that UL41 reduced the accumulation of cGAS to abrogate host recognition of viral DNA. In addition, stable knockdown of cGAS facilitated the replication of R2621 but not WT HSV-1. For the first time, HSV-1 UL41 was demonstrated to evade the cGAS/ STING-mediated DNA-sensing pathway by degrading cGAS via its RNase activity.IMPORTANCE HSV-1 is well known for its ability to evade host antiviral responses and establish a lifelong latent infection while triggering reactivation and lytic infection under stress. Currently, whether HSV-1 evades the cytosolic DNA sensing and signaling is still poorly understood. In the present study, we found that tegument protein UL41 targeted the cGAS/STING-mediated cellular DNA-sensing pathway by selectively degrading cGAS mRNA. Knockdown of endogenous cGAS could facilitate the replication of R2621 but not WT HSV-1. Furthermore, UL41 was shown for the first time to act directly on cGAS. Findings in this study could provide new insights into the host-virus interaction and help develop new approaches against HSV-1.KEYWORDS HSV-1, vhs/UL41, cGAS, DNA sensing T he innate immune system is the first line of defense against invading pathogens and is crucial for the subsequent activation of the adaptive immune response. The first step in innate immunity is to detect the invading pathogen through various pathogen recognition receptors (PRRs) which recognize pathogen-associated molecular patterns and trigger the production of type I interferon (IFN) and other antiviral factors (1, 2). Besides Toll-like receptors in the cellular membrane or endosome, Nod-like receptors and the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) in the cytoplasm, there are also several recently discovered cytosolic DNA sensors, such as cyclic GMP-AMP (cGAMP) synthase (cGAS), gamma interferon-inducible protein 16

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“…To rule out the involvement of other late proteins in viperin regulation other than UL41, Us11 was chosen, as ⌬Us11 HSV-1 had been constructed in our lab (34). Us11 is an RNA binding tegument protein that prevents the activation of protein kinase R (PKR) and oligoadenylate synthetases (OAS) and impairs type I IFN responses by antagonizing retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) (34-36).…”

mentioning

confidence: 99%

“…To establish effective infection, HSV-1 has evolved multiple mechanisms to evade host innate immunity (34,(38)(39)(40)(41)(42)(43)(44). UL41 is an mRNA-specific RNase that triggers rapid degradation of host mRNAs to facilitate the sequential expression of viral proteins (19,20,22,26,(45)(46)(47)(48).…”

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confidence: 99%

Herpes Simplex Virus 1 Counteracts Viperin via Its Virion Host Shutoff Protein UL41

Shen

Wang

et al. 2014

J Virol

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bThe interferon (IFN)-inducible viperin protein restricts a broad range of viruses. However, whether viperin plays a role during herpes simplex virus 1 (HSV-1) infection is poorly understood. In the present study, it was shown for the first time that wild-type (WT) HSV-1 infection couldn't induce viperin production, and ectopically expressed viperin inhibited the replication of UL41-null HSV-1 but not WT viruses. The underlying molecular mechanism is that UL41 counteracts viperin's antiviral activity by reducing its mRNA accumulation. Viperin is a highly conserved, 361-amino-acid protein. It was first identified as a gamma interferon (IFN-␥)-inducible protein which is directly induced by human cytomegalovirus (HCMV), and its constitutive expression is low (1). The viperin gene (also known as cig5 or RASD2) can also be categorized as an antiviral interferon-stimulated gene (ISG) which limits the replication of many DNA and RNA viruses (1-14). However, whether viperin plays a role during herpes simplex virus 1 (HSV-1) infection is unknown.To investigate whether HSV-1 could induce the expression of viperin, HEK293T cells were infected with wild-type (WT) HSV-1 at different multiplicities of infection (MOI) or with Sendai virus (SeV) (15). Infection with SeV induced a significant amount of viperin; however, infection with a low MOI (0.2) of HSV-1 induced only a trace amount of viperin, and infection with a moderate MOI (2) abrogated the expression of viperin (Fig. 1A).To further explore whether viperin could inhibit the replication of WT HSV-1, HEK293T cells with ectopic expression of viperin-Flag were infected with HSV-1 at an MOI of 0.2. Then cells were harvested at the time points indicated in the figures, and viral plaque assay was performed to determine viral replication (16). As a result, ectopically expressed viperin did not affect the replication of WT HSV-1 (Fig. 1B). The data from Western blot (WB) analysis also showed that viperin did not affect viral protein expression (Fig. 1C). These results demonstrated that ectopic expression of viperin failed to inhibit the replication of WT HSV-1.The aforementioned data led us to hypothesize that at least one of the HSV-1 proteins could counteract the expression of viperin. As a member of the ISGs, viperin was effectively induced by SeV ( Fig. 1) (15). With a high-throughput screen assay of all 84 proteins carried by HSV-1, dual-luciferase reporter gene assays were performed in HEK293T cells cotransfected with viperin-luciferase reporter plasmid and individual HSV-1 protein expression plasmid for 20 h and infected with SeV (17). As a result, ectopically expressed UL41 abrogated the expression of viperin; however, other HSV-1 proteins did not (data not shown). UL41 has been reported to degrade both viral and cellular mRNAs (18)(19)(20)(21)(22)(23)(24)(25)(26). Recently, mRNA of tetherin has been reported to be degraded by UL41 (27). Meanwhile, ICP0, an E3 ubiquitin ligase, promotes degradation of many cellular antiviral proteins, such as IRF3, IRF7, IFI16, and ATRX ...

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Herpes Simplex Virus 1 Tegument Protein US11 Downmodulates the RLR Signaling Pathway via Direct Interaction with RIG-I and MDA-5

Cited by 139 publications

References 97 publications

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

Herpes Simplex Virus 1 Counteracts Viperin via Its Virion Host Shutoff Protein UL41

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