Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Inhibits Beta Interferon Production by Deubiquitinating TRAF3

Wang, Shuai; Wang, Kezhen; Li, Jie; Zheng, Chunfu

doi:10.1128/jvi.01211-13

Cited by 114 publications

(131 citation statements)

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“…Recently, an increasing number of studies has indicated that TRAF3 is a potential target for impairing innate immunity. It is likely that herpes simplex virus 1 or chlamydia pneumoniae expresses a unique protein for preventing TRAF3 from activating TBK1 (Wang et al, 2013;Wolf and Fields 2013). In the present study, chTRAF3 and IFN-β transcripts from CEF cells challenged with NDV vaccine strain Mukteswar were much stronger than NDV F48E9 treatment, suggesting that chicken TRAF3 plays an important role in NDV F48E9 disarm innate immune responses.…”

Section: Discussionmentioning

confidence: 44%

Molecular cloning and expression analysis of TRAF3 in chicken

Yang¹,

Feng²,

Zeng³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a crucial regulator that suppresses c-Jun N-terminal kinase and non-canonical nuclear factor-kB signaling, but facilitates type I interferon production. To determine TRAF3 function in innate immune responses among birds, particularly chicken, we cloned and characterized the chicken TRAF3 gene (chTRAF3) and detected its tissue expression profile in chicken. We also detected the differential expression of chTRAF3 and its downstream gene interferon-b (IFN-β) upon different stimuli in primary chicken embryo fibroblast cells. Two chTRAF3 gene products, chTRAF3-1 and chTRAF3-2, can be produced by alternative splicing. The full-length coding sequence of chTRAF3 (chTRAF3-1) was 1704 base pairs and encoded a protein of 567 amino acids with high identity to TRAF3 homologs from mammals and other birds. The deduced amino acid sequence showed typical characteristics of TRAFs, with a RING finger domain, 2 zf-TRAF motifs, and a MATH domain. Quantitative real-time polymerase chain reaction analysis revealed broad expression of chTRAF3 in all detected tissues, with abundant expression in the spleen, thymus, lung, and (2015) small intestine. Expression of chTRAF3 was significantly upregulated in a time-and concentration-dependent manner in chicken embryo fibroblast cells challenged with poly I:C or poly dA-dT. Furthermore, chTRAF3 and IFN-β mRNA expression from chicken embryo fibroblast cells challenged with Newcastle disease virus F48E9 suffered intense suppression compared with Newcastle disease virus Mukteswar infection. Our results indicate that chTRAF3 plays important roles in defending against both RNA and DNA virus infection.

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Section: Discussionmentioning

confidence: 44%

Molecular cloning and expression analysis of TRAF3 in chicken

Yang¹,

Feng²,

Zeng³

et al. 2015

Genet. Mol. Res.

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“…The aforementioned results raised the hypothesis that UL36USP might deubiquitinate IB␣ to block NF-B transcription. It has been reported that the residue Cys65 in UL36USP of the HSV-1 KOS strain is indispensable for DUB activity (23), whereas for the HSV-1 F strain in this study, mutation of Cys40 to Ala abrogates the deubiquitinase activity of UL36USP (24). To substantiate our speculation, we first examined whether UL36USP could inhibit IB␣ degradation during HSV-1 infection.…”

Section: Ul36usp Inhibited Cgas-sting-mediated Ifn-␤ and Nf-b Activatmentioning

confidence: 50%

“…As the largest tegument protein encoded by HSV-1, UL36 contains an approximately 420-amino-acid deubiquitinase (DUB) domain in its N terminus, also known as UL36USP, which is cleaved from full-length UL36 and can be detected at 12 h after viral infection (23). Our previous study demonstrated that UL36USP inhibits RIG-I-like receptor (RLR)-induced IFN-␤ production by removing the Lys63-linked ubiquitin chains from TNF receptor-associated factor 3 (TRAF3) and blocking IRF3 activation (24). It has been reported that UL36USP could particularly cleave Lys48-linked polyubiquitin chains but not the conjugates of ISGylation, Neddylation, SUMOylation, or Lys63-linked polyubiquitination (23).…”

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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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“…This necessarily implicates the prior addition of ubiquitin as a factor in disease progression, either as part of the virus neuroinvasive program or as a cellular defense mechanism that is overcome by the DUB. Although several substrates of the DUB have been identified, how this enzyme promotes the potent neuroinvasive property of these viruses is unknown (23)(24)(25)(26)(27)(28)(29)(30). To elucidate the role of the DUB, we set out to examine the role of ubiquitination during neuroinvasive herpesvirus infection.…”

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confidence: 99%

Dynamic ubiquitination drives herpesvirus neuroinvasion

Huffmaster

Sollars

Richards

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Neuroinvasive herpesviruses display a remarkable propensity to enter the nervous system of healthy individuals in the absence of obvious trauma at the site of inoculation. We document a repurposing of cellular ubiquitin during infection to switch the virus between two invasive states. The states act sequentially to defeat consecutive host barriers of the peripheral nervous system and together promote the potent neuroinvasive phenotype. The first state directs virus access to nerve endings in peripheral tissue, whereas the second delivers virus particles within nerve fibers to the neural ganglia. Mutant viruses locked in either state remain competent to overcome the corresponding barrier but fail to invade the nervous system. The herpesvirus “ubiquitin switch” may explain the unusual ability of these viruses to routinely enter the nervous system and, as a consequence, their prevalence in human and veterinary hosts.

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Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Inhibits Beta Interferon Production by Deubiquitinating TRAF3

Cited by 114 publications

References 80 publications

Molecular cloning and expression analysis of TRAF3 in chicken

Molecular cloning and expression analysis of TRAF3 in chicken

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

Dynamic ubiquitination drives herpesvirus neuroinvasion

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