Evasion of host antiviral innate immunity by HSV-1, an update

Su, Chenhe; Zhan, Guoqiang; Zheng, Chunfu

doi:10.1186/s12985-016-0495-5

Cited by 133 publications

(126 citation statements)

References 109 publications

(109 reference statements)

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“…Therefore, HSV-1 also evolved strategies to evade NF-B signaling during infection and to balance the promoting and suppressing effects for its propagation. Studies have reported that HSV-1 uses a variety of proteins, mostly tegument proteins, to maintain effective infection (34). ICP0, an E3 ubiquitin ligase, disrupts NF-B activation by abrogating p65 nuclear translocation and promoting p50 to proteasomal degradation (35).…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-κB Activation in DNA Sensing Signal Pathway

et al. 2017

J Virol

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The DNA sensing pathway triggers innate immune responses against DNA virus infection, and NF-B signaling plays a critical role in establishing innate immunity. We report here that the herpes simplex virus 1 (HSV-1) ubiquitinspecific protease (UL36USP), which is a deubiquitinase (DUB), antagonizes NF-B activation, depending on its DUB activity. In this study, ectopically expressed UL36USP blocked promoter activation of beta interferon (IFN-␤) and NF-B induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). UL36USP restricted NF-B activation mediated by overexpression of STING, TANKbinding kinase 1, IB kinase ␣ (IKK␣), and IKK␤, but not p65. UL36USP was also shown to inhibit IFN-stimulatory DNA-induced IFN-␤ and NF-B activation under conditions of HSV-1 infection. Furthermore, UL36USP was demonstrated to deubiquitinate IB␣ and restrict its degradation and, finally, abrogate NF-B activation. More importantly, the recombinant HSV-1 lacking UL36USP DUB activity, denoted as C40A mutant HSV-1, failed to cleave polyubiquitin chains on IB␣. For the first time, UL36USP was shown to dampen NF-B activation in the DNA sensing signal pathway to evade host antiviral innate immunity.IMPORTANCE It has been reported that double-stranded-DNA-mediated NF-B activation is critical for host antiviral responses. Viruses have established various strategies to evade the innate immune system. The N terminus of the HSV-1 UL36 geneencoded protein contains the DUB domain and is conserved across all herpesviruses. This study demonstrates that UL36USP abrogates NF-B activation by cleaving polyubiquitin chains from IB␣ and therefore restricts proteasome-dependent degradation of IB␣ and that DUB activity is indispensable for this process. This study expands our understanding of the mechanisms utilized by HSV-1 to evade the host antiviral innate immune defense induced by NF-B signaling.KEYWORDS HSV-1, DNA sensor, UL36, NF-B, IB␣ C ells have developed plenty of ways to govern their homeostasis, and the recognition of double-stranded DNA (dsDNA) by DNA sensors is a central host cellular defense against DNA virus infection. Among these DNA sensors, cyclic GMP-AMP synthase (cGAS), which is a nucleotidyltransferase, has been demonstrated to be the predominant cytosolic DNA sensor. Upon binding to DNA fragments, cGAS utilizes GTP and ATP to produce cyclic-GMP-AMP (cGAMP) through its enzymatic activity, and cGAMP activates an endoplasmic reticulum (ER)-resident receptor, stimulator of interferon genes (STING) (1). Activated STING then recruits TANK-binding kinase 1 (TBK1) and traffics from the ER to a perinuclear endosomal compartment, leading to the activation of transcription factors NF-B and interferon (IFN) regulatory factor 3 (IRF3), which induce IFN-␤ production (1-4).

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Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-κB Activation in DNA Sensing Signal Pathway

et al. 2017

J Virol

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“…During this process, HSV can activate multiple signal transduction pathways, including Nuclear Factor kappa B (NF-κB), interferon (IFN) Regulatory Factors (IRFs) and Mitogen-Activated Protein Kinase (MAPK) pathways, resulting in induction of cytokine production in HSV-infected cells [14,15]. Stimulation of NF-κB and IRF pathways occur when HSV glycoprotein H/L complex interacts with the αvβ 3-integrin signaling pathway, which results in induction of type I IFNs [16].…”

Section: Host Responses Against Hsv Infectionmentioning

confidence: 99%

Oncolytic herpes simplex virus interactions with the host immune system

Saha

Wakimoto

Rabkin

2016

Current Opinion in Virology

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Oncolytic viruses (OVs), like oncolytic herpes simplex virus (oHSV), are genetically engineered to selectively replicate in and kill cancer cells, while sparing normal cells. Initial OV infection, cell death, and subsequent OV propagation within the tumor microenvironment leads to a cascade of host responses (innate and adaptive), reflective of natural anti-viral immune responses. These host-virus interactions are critical to the balance between OV activities, anti-viral immune responses limiting OV, and induction of anti-tumor immunity. The host response against oHSV is complex, multifaceted, and modulated by the tumor microenvironment and immunosuppression. As a successful pathogen, HSV has multiple mechanisms to evade such host responses. In this review, we will discuss these mechanisms and HSV evasion, and how they impact oHSV therapy.

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“…As a master of immune evasion, HSV-1 has evolved multiple strategies to counteract host antiviral responses (14). Although much progress has been made in understanding the mechanisms of HSV-1-mediated immune evasion, most of these findings focused on Toll-like receptor-and RLR-mediated signaling pathways, and our understanding of how HSV-1 evades cellular DNA sensing pathways is still quite limited.…”

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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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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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Evasion of host antiviral innate immunity by HSV-1, an update

Cited by 133 publications

References 109 publications

Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-κB Activation in DNA Sensing Signal Pathway

Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-κB Activation in DNA Sensing Signal Pathway

Oncolytic herpes simplex virus interactions with the host immune system

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

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