Herpes simplex virus 1 infection dampens the immediate early antiviral innate immunity signaling from peroxisomes by tegument protein VP16
© The Author(s). 2017
Received: 6 December 2016
Accepted: 15 February 2017
Published: 21 February 2017
Herpes simplex virus 1 (HSV-1) is an archetypal member of the alphaherpesvirus subfamily with a large genome encoding over 80 proteins, many of which play a critical role in virus-host interactions and immune modulation. Upon viral infections, the host cells activate innate immune responses to restrict their replications. Peroxisomes, which have long been defined to regulate metabolic activities, are reported to be important signaling platforms for antiviral innate immunity. It has been verified that signaling from peroxisomal MAVS (MAVS-Pex) triggers a rapid interferon (IFN) independent IFN-stimulated genes (ISGs) production against invading pathogens. However, little is known about the interaction between DNA viruses such as HSV-1 and the MAVS-Pex mediated signaling.
HSV-1 could activate the MAVS-Pex signaling pathway at a low multiplicity of infection (MOI), while infection at a high MOI dampens MAVS-Pex induced immediately early ISGs production. A high-throughput screen assay reveals that HSV-1 tegument protein VP16 inhibits the immediate early ISGs expression downstream of MAVS-Pex signaling. Moreover, the expression of ISGs was recovered when VP16 was knockdown with its specific short hairpin RNA.
HSV-1 blocks MAVS-Pex mediated early ISGs production through VP16 to dampen the immediate early antiviral innate immunity signaling from peroxisomes.
KeywordsHSV-1 VP16 MAVS-Pex Immune evasion
The host innate immune system plays an important role in detecting the invading pathogens. Conserved pathogen-associated molecular patterns from viruses are initially recognized by multiple immune sensors that are referred to as pattern recognition receptors (PRRs) [1–3]. Besides Toll-like receptors in the cellular membrane or endosome and Nod-like receptors in the cytoplasm, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) such as RIG-I and melanoma differentiation-associated gene 5 (MDA-5) are able to detect 5′-triphosphate-containing short double-stranded RNA (dsRNA) and long dsRNA respectively and activate the expression of type I interferons (IFNs) and IFN-stimulated genes (ISGs) [4–8]. RLRs can detect both viral RNA and RNA polymerase III-mediated transcription of microbial DNA [8–10]. Additionally, MDA-5 was reported to be a primary mediator of HSV recognition using small interfering RNA knockdown in HSV-infected macrophages . Upon recognition of viral RNA, RIG-I and MDA-5 interact with the mitochondrial antiviral signaling protein (MAVS, also known as IPS-1, VISA, and CARDIF), which then leads to the production of IFNs and ISGs [12, 13].
As the adaptor protein downstream of the RLR-dependent signaling pathway, MAVS was reported to locate on mitochondria, peroxisomes and mitochondria-associated membranes of the endoplasmic reticulum [14–16]. Peroxisomes have been established to be metabolic regulation organelles for a long time, which control the metabolism of lipids and reactive oxygen species [17–19]. Surprisingly, these organelles were also revealed to be important signaling platforms for antiviral innate immunity. Upon viral infection, peroxisomal MAVS (MAVS-Pex) triggers an immediate early induction of ISGs, which is type I IFN-independent, whereas mitochondrial MAVS shows a delayed and sustained antiviral effect based on the induction of type I IFNs and ISGs . In addition, MAVS-Pex is also identified to activate type III IFN expression .
Herpes Simplex Virus 1 (HSV-1) is an archetypal member of the alphaherpesvirinae subfamily, which encodes over 80 proteins. VP16, a 65-kDa tegument protein of HSV-1, was reported to have various functions, including transcriptional activation of viral immediate early genes, downregulation of the virion host shutoff protein and participation in viral egress downstream of the initial envelopment [21–24]. Furthermore, our previous study has demonstrated that VP16 also downregulates the production of IFN-β in RLR signaling pathway .
A variety of ISGs function as antiviral effectors. Viperin (also known as cig5 or RASD2), a highly conserved and well-characterized ISG protein, limits the replication of many DNA and RNA viruses [16, 26–37]. To survive within the infected host, HSV-1 has evolved multiple strategies to counteract host antiviral innate immune responses through its numerous proteins [25, 38–44]. In this study, we demonstrated for the first time that HSV-1 tegument protein VP16 dampened the MAVS-Pex signaling and the expression of the immediate early ISGs, such as viperin.
HSV-1 infection triggers a MAVS-Pex-dependent early induction of viperin
HSV-1 infection at a high multiplicity of infection (MOI) dampens the immediate early induction of viperin triggered by MAVS-Pex
VP16 inhibits the early induction of viperin from MAVS-Pex
Knockdown of VP16 restores the immediate early innate antiviral signaling triggered by MAVS-Pex or HSV-1 infection
As the first line of defense against infectious threats, the innate immune system represents a conserved role in response to virus invasion and achieves their detections through PRRs. In RLRs signaling pathway, MAVS was originally reported to reside on mitochondria and bound to RLRs to initiate the downstream activation of NF-κB and interferon regulatory factors (IRFs) , which then translocated to the nucleus and activated the transcription of IFNs and ISGs. Nevertheless, MAVS was also reported to reside on peroxisomes, where it could trigger a rapid, IFN-independent ISG response, completely different from that of the mitochondrial MAVS .
As a double-strand DNA virus, HSV-1 evolved multiple mechanisms to evade the host innate immunity and establish its infection . The virion host shutoff protein blocks cellular antiviral proteins, like tetherin, viperin, and zinc finger antiviral protein, by targeting their mRNA for degradation [47–49]. Us11, an RNA binding tegument protein, interferes with the interaction between MAVS and RIG-I or MDA-5, thus dampens IRF3 activation and IFN production . UL36, a ubiquitin-specific protease, inhibits IFN production by deubiquitinating TRAF3 to prevent recruitment of TBK1 . Us3, which hyperphosphorylates IRF3 and p65, blocks their nuclear translocation and thus down regulates IFN-β production . ICP0, an E3 ubiquitin ligase, disrupts NF-κB activation by abrogating the nuclear translocation of p65 and degrading p50 through ubiquitin-proteasome pathway . ICP34.5, best known for its ability to inhibit the IFN-inducible kinase PKR, also dampens IFN production by binding and sequestering TBK-1, which phosphorylates IRF3 . VP24, a serine protease of HSV-1, blocks DNA sensing signal pathway via abrogating the interaction between TBK1 and IRF3 .
Although there are plenty of HSV-1 proteins which block the IFN-β signaling pathway, the role of HSV-1 on the MAVS-Pex signaling has not been reported. Here we demonstrate for the first time that HSV-1 is able to activate the early antiviral signaling from peroxisomes. VP16, which is encoded by UL48 gene, has various functions in viral growth and infection. Our previous study showed that VP16 could abrogate the production of IFN-β, which presented a critical role of VP16 in mitochondrial MAVS signaling . In this present study, we demonstrated another important effect of VP16 to abrogate the early expression of ISGs in the IFN-independent MAVS-Pex signaling pathway, which was characterized by viperin. As an abundant tegument protein, VP16 was released into host cells upon infection, dampened the immediate early antiviral immunity from peroxisomes in host cells and facilitated the proliferation of HSV-1. In addition, we found that VP16 could also inhibit the activation of viperin promoter induced by IRF3 and IRF1, two central regulators of IFN independent ISG expression which act downstream of MAVS-Pex (data not shown). And previous studies in our lab have reported that VP16 interacted with the CREB binding protein (CBP) coactivator and efficiently inhibited the formation of the transcriptional complexes IRF-3-CBP . Therefore, we hypothesized that VP16 might act downstream of MAVS-Pex through a similar mechanism, interacting with coactivators of IRFs, but not direct on MAVS-Pex. However, until now the signal pathway downstream of MAVS-Pex is still largely unknown, so identification of VP16 target in the MAVS-Pex pathway and revealing the underlying molecular mechanisms require further investigation.
In summary, our studies define for the first time the contribution of HSV-1 tegument protein VP16 in the evasion of the immediate early antiviral response through MAVS-Pex signaling. This finding leads to a better understanding of the mechanisms of VP16 in dampening the host antiviral signaling and uncovers a new method of HSV-1 invasion against early-stage defense in host cells.
Cells, viruses, antibodies and reagents
HEK293, MEF and HEK293T cells were grown in Dulbecco’s modified minimal essential medium (DMEM) (Gibco-BRL) supplemented with 10% fetal bovine serum (FBS) as described previously [38, 52]. The WT HSV-1 F strain virus was propagated in Vero cells as described previously . Rabbit anti-UL42 polyclonal antibody was made by GL Biochem Ltd. (Shanghai, China). Mouse anti-HA monoclonal antibody (mAb), anti-Flag mAb and anti-β-actin mAb were purchased from Abmart (Shanghai, China). Mouse anti-VP16 mAb was purchased from Santa Cruz Biotechnology (CA, USA). Rabbit anti-viperin polyclonal antibody was purchased from Abcam (Cambridge, MA, USA). BFA was purchased from Selleck (TX, USA). MAVS-KO MEF cells were provided by Dr. Chen Wang.
All enzymes used for cloning procedures were purchased from Vazyme (Nanjing, China). MAVS-Pex-YFP and MAVS-Pex-HA plasmids were subclones from MAVS-Pex-GFP (Addgene, MA, USA). Renilla luciferase plasmid pRL-TK (expressing thymidine kinase [TK]) was purchased from Promega (Madison, WI, USA). Oligonucleotides encoding shRNA-VP16 was synthesized and inserted into the pSuper.retro.puro vector (Oligoengine, LA, USA). Viperin reporter plasmids Viperin-Luc and Vig1-Luc were gifts from Dr. Katherine A. Fitzgerald. Plasmid PTS1-DsRed was a gift from Dr. Jonathan C. Kagan.
Transfection, BFA treatment and DLR assay
MEF cells were transfected with Lipofectamine® LTX (Invitrogen, CA, USA) according to the manufacturers’ recommendations. HEK293 cells were preincubated with 50 ng/ml BFA and infected with or without WT HSV-1 in the presence of BFA. At 2 h post infection, the supernatants were discarded and replaced by cell culture containing 50 ng/ml BFA, and cells were cotransfected with viperin luciferase reporter plasmid Viperin-Luc and internal control pRL-TK, with or without indicated plasmids in the presence of BFA, by standard calcium phosphate precipitation . Luciferase assays were performed with a dual-specific luciferase assay kit (Promega) as previously described [38, 44].
RNA isolation, qRT-PCR
Total RNA was extracted from HEK293 cells with TRIzol (Invitrogen, CA, USA) according to the manufacturer’s manual. Samples were digested with DNase I and subjected to reverse transcription. The cDNA was used as a template for qRT-PCR to detect the accumulation of indicated mRNA as previously described . The primers used for RT-PCR analysis are as follows: Viperin tggtgaggttctgcaaagtag (forward) and tcacaggagatagcgagaatgtc (reverse), GAPDH tgacctcaactacatggtttacatgt (forward) and agggatctcgctcctggaa (reverse).
Western blot analysis
Data are represented as mean ± SD when indicated, and Student’s T-test was used for all statistical analyses with the GraphPad Prism 5.0 software. Differences between groups were considered significant when P-value was <0.05.
Herpes simplex virus 1
Mitochondrial antiviral signaling protein
Multiplicity of infection
We thank Dr. Katherine A. Fitzgerald for viperin reporter plasmids, Dr. Chen Wang for MAVS-KO MEF cells, and Dr. Jonathan C. Kagan for PTS1-DsRed plasmid. This work was supported by grants from the National Natural Science Foundation of China (81371795 and 81571974) and Innovative Research Team in Soochow University (PCSIRT, IRT 1075).
CZ and CS conducted the experiments and drafted the manuscript. CZ provided overall supervision and financial support and edited the manuscript. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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