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

Abstract

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.

HSV-1 and Zika Virus but Not SARS-CoV-2 Replicate in the Human Cornea and Are Restricted by Corneal Type III Interferon

“…This led to consistently enhanced replication of HSV-1 in all infected human donor samples, with approximately 10-fold higher levels of infectious virus by 72 h after infection (6.1 × 10 4 PFU/mL in anti-IFNλR1 treated corneas versus 6.3 × 10 3 PFU/mL in control mAb-treated corneas, p < 0.005) ( Figure 3 H). HSV-1 blocks the type I IFN response in order to facilitate viral replication ( Yuan et al., 2018 ), so we reasoned that HSV-1 may similarly antagonize IFN-λ production or signaling. Quantitation of IFNL1 and IFNL2 mRNA with and without HSV-1 revealed that HSV-1 infection reduces expression of IFNL2 within the first 24 h after infection ( Figures 3 I and 3J).…”

Inflammation, Infectious Triggers, and Parkinson's Disease

“…The role of viral infections in diverging signaling pathways which regulate the establishment of innate immunity, such as those including proinflammatory molecules and DNA sensing, has been long hypothesized in PD pathogenesis. Herpes simplex virus 1 (HSV-1) encodes a ubiquitin-specific protease (UL36USP) which subverts type I IFN-mediated signaling, in particular IFN-β-induced signaling, independently from its deubiquitinase (DUB) activity (48). HSV-1 UL24 has the ability to inhibit the activation of IFN-β and interleukin-6 (IL-6) promoters mediated by cyclic GMP-AMP synthase (cGAS)—a newly identified foreign DNA sensor, and the interferon-stimulatory DNA-mediated IFN-β and IL-6 production during HSV-1 infection.…”

HSV-1 single-cell analysis reveals the activation of anti-viral and developmental programs in distinct sub-populations

“…One such example is the seemingly complex relation between HSV-1 infection and type I interferon (IFN) signaling. The picture that emerges from population-level measurements is paradoxical, with wildtype HSV-1 infection both clearly activating (Gianni et al, 2013; Hu et al, 2016; Liu et al, 2016; Reinert et al, 2016) and clearly repressing (Lin et al, 2004; Johnson et al, 2008; Kew et al, 2013; Johnson and Knipe, 2010; Su et al, 2016; Christensen et al, 2016; Manivanh et al, 2017; Yuan et al, 2018; Chiang et al, 2018) the type I IFN pathway. Such discrepancies might be resolved with the use of single-cell measurements.…”