Herpes Simplex Virus 1 Tegument Protein UL41 Counteracts IFIT3 Antiviral Innate Immunity

Abstract

The interferon-induced protein with tetratricopeptide repeat 3 (IFIT3 or ISG60) is a host-intrinsic antiviral factor that restricts many instances of DNA and RNA virus replication. Herpes simplex virus 1 (HSV-1), a DNA virus bearing a large genome, can encode many viral proteins to counteract the host immune responses. However, whether IFIT3 plays a role upon HSV-1 infection is little known. In this study, we show for the first time that HSV-1 tegument protein UL41, a viral endoribonuclease, plays an important role in inhibiting the antiviral activity of IFIT3. Here, we demonstrated that ectopically expressed IFIT3 could restrict the replication of vesicular stomatitis virus (VSV) but had little effect on the replication of wild-type (WT) HSV-1. Further study showed that WT HSV-1 infection downregulated the expression of IFIT3, and ectopic expression of UL41, but not the immediate-early protein ICP0, notably reduced the expression of IFIT3. The underlying molecular mechanism was that UL41 diminished the accumulation of IFIT3 mRNA to abrogate its antiviral activity. In addition, our results illustrated that ectopic expression of IFIT3 inhibited the replication of UL41-null mutant virus (R2621), and stable knockdown of IFIT3 facilitated its replication. Taking these findings together, HSV-1 was shown for the first time to evade the antiviral function of IFIT3 via UL41. IMPORTANCEThe tegument protein UL41 of HSV-1 is an endoribonuclease with the substrate specificity of RNase A, which plays an important role in viral infection. Upon HSV-1 infection, interferons are critical cytokines that regulate immune responses against viral infection. Host antiviral responses are significantly boosted or crippled in the presence or absence of IFIT3; however, whether IFIT3 plays a role during HSV-1 infection is still unknown. Our data show for the first time that IFIT3 has little effect on HSV-1 replication, as UL41 decreases the accumulation of IFIT3 mRNA and subverts its antiviral activity. This study identifies IFIT3 as a novel target of the tegument protein UL41 and provides new insight into HSV-1-mediated immune evasion.

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

“…In this study, we found that UL41 targeted and reduced cGAS expression by degrading its mRNA. In addition, we and other researchers have demonstrated that UL41 is also involved in HSV-1-mediated immune evasion by targeting several IFN-stimulated genes (ISGs) (17,20,21). Therefore, UL41 is a broad innate immune inhibitor and can block cGAS/STING-mediated IFN signaling at multiple steps.…”

“…All enzymes used for cloning procedures were purchased from Vazyme (Nanjing, China). Small hairpin RNA specific for cGAS (shcGAS) and scrambled small hairpin RNA as a negative control (shNC) were cloned into pSUPER.retro.puro vector (Oligoengine, LA) to yield pSUPERshcGAS and pSUPER-shNC plasmids, respectively, as described in our previous study (21). Commercial reporter plasmid pRL-TK (RL stands for Renilla luciferase, and TK stands for thymidine kinase) was purchased from Promega Corporation (Madison, WI).…”

“…HSV-1 tegument protein UL41, also known as the virion host shutoff protein, is an endoribonuclease with the activity of mRNA-specific RNase and plays a role in HSV-1-mediated evasion of host antiviral responses (16)(17)(18)(19)(20)(21). UL41 triggers selective degradation of host mRNAs to facilitate viral infection.…”

One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

“…lacking UL41 expression was impaired in the presence of ZAP (Su et al, 2015). Similarly, IFIT3 was reported to have no effect on HSV-1 infection (Jiang et al, 2016). As for ZAP, human IFIT proteins with the family members IFIT1, IFIT2, and IFIT3 belong to the subgroup of non-canonical ISGs (Schoggins et al, 2014).…”

“…Notably, IFIT3 inhibits the replication of HSV-1 lacking UL41 expression, underlining the importance of UL41 in evading the antiviral effect of IFIT3. The authors showed that UL41 degrades IFIT3 mRNA, but not that of IFIT1 or IFIT2 (Jiang et al, 2016), indicating that HSV-1 may specifically target IFIT3 to prevent the MAVS-TBK1 association, thus suppressing downstream signalling.…”