Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response

Zhang, Rui; Xu, Aotian; Qin, Chao; Zhang, Qiong; Chen, Shifan; Lang, Yue; Wang, Mengdong; Li, Chuang; Feng, Wen-hai; Jiang, Zhengfan; Tang, Jun

doi:10.1128/jvi.01148-17

Cited by 61 publications

(60 citation statements)

References 42 publications

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“…Recently, pseudorabies virus, a swine alphaherpesvirus, has been uncovered in which viral protein UL50 accelerates IFNAR1 degradation to avoid type I IFN responses. It also demonstrated that HSV-1 UL50 possesses similar activity, although the activity is milder (46). In fact, a previous study has already provided evidence that HSV-1 infection induces the degradation of IFNAR1 (13).…”

Section: Discussionmentioning

confidence: 74%

Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity

Yuan

You

et al. 2018

J Virol

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Type I interferons (IFNs), as major components of the innate immune system, play a vital role in host resistance to a variety of pathogens. Canonical signaling mediated by type I IFNs activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway through binding to the IFN-α/β receptor (IFNAR), resulting in transcription of IFN-stimulated genes (ISGs). However, viruses have evolved multiple strategies to evade this process. Here, we report that herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP) abrogates the type I IFN-mediated signaling pathway independent of its deubiquitinase (DUB) activity. In this study, ectopically expressed UL36USP inhibited IFN-β-induced activation of ISRE promoter and transcription of ISGs, and overexpression of UL36USP lacking DUB activity did not influence this effect. Furthermore, UL36USP was demonstrated to antagonize IFN-β-induced activation of JAKs and STATs via specifically binding to the IFNAR2 subunit and blocking the interaction between JAK1 and IFNAR2. More importantly, knockdown of HSV-1 UL36USP restored the formation of JAK1-IFNAR2 complex. These findings underline the roles of UL36USP-IFNAR2 interaction in counteracting the type I IFN-mediated signaling pathway and reveal a novel evasion mechanism of antiviral innate immunity by HSV-1. Type I IFNs mediate transcription of numerous antiviral genes, creating a remarkable antiviral state in the host. Viruses have evolved various mechanisms to evade this response. Our results indicated that HSV-1 encodes a ubiquitin-specific protease (UL36USP) as an antagonist to subvert type I IFN-mediated signaling. UL36USP was identified to significantly inhibit IFN-β-induced signaling independent of its deubiquitinase (DUB) activity. The underlying mechanism of UL36USP antagonizing type I IFN-mediated signaling was to specifically bind with IFNAR2 and disassociate JAK1 from IFNAR2. For the first time, we identify UL36USP as a crucial suppressor for HSV-1 to evade type I IFN-mediated signaling. Our findings also provide new insights into the innate immune evasion by HSV-1 and will facilitate our understanding of host-virus interplay.

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Section: Discussionmentioning

confidence: 74%

Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity

Yuan

You

et al. 2018

J Virol

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“…DAPI (4,6-diamidino-2-phenylindole) was purchased from Beyotime Institute of Biotechnology. The antibodies against PRV TK, PRV US3, PRV EP0 were described previously (30, 32, 33). Mouse polyclonal antibodies against PRV IE180, VP5 and gD were raised in mice individually with the 1-666aa, 710-1280aa, 240-400aa region of each protein as antigens.…”

Section: Methodsmentioning

confidence: 99%

Swine Promyelocytic Leukemia Isoform II Inhibits Pseudorabies Virus Infection by Suppressing Viral Gene Transcription in PML-NBs

Yu¹,

Xu²,

Lang³

et al. 2020

Preprint

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22Promyelocytic leukaemia nuclear bodies (PML-NBs) possess an important intrinsic 23 antiviral activity against a-herpesvirus infection. PML is the structural backbone of 24 NBs, comprising different isoforms. However, the contribution of each isoform to 25 a-herpesvirus restriction is not well understood. Here, we report the role of PML-26NBs and swine PML (sPML) isoforms in pseudorabies virus (PRV) infection in its 27 natural host swine cells. We found that sPML-NBs exhibit an anti-PRV activity in 28 the context of increasing the expression level of endogenous sPML. Of four sPML 29 isoforms cloned and examined, only isoform sPML-II/IIa, not sPML-I and IVa, 30 expressed in a sPML knockout cells inhibits PRV infection. Both the unique 7b 31 region of sPML-II and sumoylation-dependent normal formation of PML-NBs are 32 required. 7b possesses a transcriptional repression activity and suppresses viral 33 gene transcription during PRV infection with the cysteine residue 589 and 599 34 being critically involved. We conclude that sPML-NBs inhibit PRV infection by 35 repressing viral gene transcription through the 7b region of sPML-II. 36 IMPORTANCE 37PML-NBs are nuclear sites that mediate the antiviral restriction of a-herpesvirus 38 gene expression and replication. However, the contrition of each PML isoform to 39 this activity of PML-NBs is not well characterized. Using PRV and its natural host 40 swine cells as a system, we have discovered that the unique C-terminus of sPML 41 isoform II is required for PML-NBs to inhibit PRV infection by directly engaging in 42 repression of viral gene transcription. Our study not only confirms in swine cells 43 that PML-NBs have an anti-viral function, but also presents a mechanism to 44 suggest that PML-NBs inhibit viral infection in an isoform specific manner. 45 MATERIALS AND METHODS 108Cell culture and viruses 109

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“…This results in decreased IRF3 activation and subsequently lower levels of type I IFN production ( 132 ). Moreover, UL50 proteins from HSV-1 and PseudoRabies Virus (PRV) induce the lysosomal degradation of the Type I IFN receptor 1 ( 133 ). Although the mechanism is not yet deciphered, it also occurs in HCV infection ( 110 ).…”

Section: Viral Manipulation Of Autophagy-dependent Regulation Of Innamentioning

confidence: 99%

Regulation of Innate Immune Responses by Autophagy: A Goldmine for Viruses

2020

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Autophagy is a lysosomal degradation pathway for intracellular components and is highly conserved across eukaryotes. This process is a key player in innate immunity and its activation has anti-microbial effects by directly targeting pathogens and also by regulating innate immune responses. Autophagy dysfunction is often associated with inflammatory diseases. Many studies have shown that it can also play a role in the control of innate immunity by preventing exacerbated inflammation and its harmful effects toward the host. The arms race between hosts and pathogens has led some viruses to evolve strategies that enable them to benefit from autophagy, either by directly hijacking the autophagy pathway for their life cycle, or by using its regulatory functions in innate immunity. The control of viral replication and spread involves the production of anti-viral cytokines. Controlling the signals that lead to production of these cytokines is a perfect way for viruses to escape from innate immune responses and establish successful infection. Published reports related to this last viral strategy have extensively grown in recent years. In this review we describe several links between autophagy and regulation of innate immune responses and we provide an overview of how viruses exploit these links for their own benefit.

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Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response

Cited by 61 publications

References 42 publications

Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity

Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity

Swine Promyelocytic Leukemia Isoform II Inhibits Pseudorabies Virus Infection by Suppressing Viral Gene Transcription in PML-NBs

Regulation of Innate Immune Responses by Autophagy: A Goldmine for Viruses

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