Differential importance of highly conserved residues in UL24 for herpes simplex virus 1 replication in vivo and reactivation

Leiva‐Torres, Gabriel André; Rochette, Pierre-Alexandre; Pearson, Angela

doi:10.1099/vir.0.017921-0

Cited by 23 publications

(28 citation statements)

References 35 publications

(37 reference statements)

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“…Notably, in vivo animal models provide several lines of evidence to support the idea that Herpes_UL24 family proteins (HSV-1, HSV-2, EHV-1, and HMV-68) may be pathogenic determinants for neurological and lung infections and may be critical in the efficient reactivation of latent virus from sensory ganglia (82-84, 86, 87). Moreover, the conserved N-terminal region (HSV-1) is required for pathogenic manifestation (86). Taking all these data together, we conclude that the N-terminal conserved region of the Herpes_UL24 family contributes to aggregation, the usurping of the UPS, potential endonuclease activity, and pathogenic effects.…”

Section: Discussionmentioning

confidence: 93%

Human Cytomegalovirus UL76 Elicits Novel Aggresome Formation via Interaction with S5a of the Ubiquitin Proteasome System

Lin

Jiang

Wang

et al. 2013

J Virol

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dHCMV UL76 is a member of a conserved Herpesviridae protein family (Herpes_UL24) that is involved in viral production, latency, and reactivation. UL76 presents as globular aggresomes in the nuclei of transiently transfected cells. Bioinformatic analyses predict that UL76 has a propensity for aggregation and targets cellular proteins implicated in protein folding and ubiquitinproteasome systems (UPS). Furthermore, fluorescence recovery after photobleaching experiments suggests that UL76 reduces protein mobility in the aggresome, which indicates that UL76 elicits the aggregation of misfolded proteins. Moreover, in the absence of other viral proteins, UL76 interacts with S5a, which is a major receptor of polyubiquitinated proteins for UPS proteolysis via its conserved region and the von Willebrand factor type A (VWA) domain of S5a. We demonstrate that UL76 sequesters polyubiquitinated proteins and S5a to nuclear aggresomes in biological proximity. After knockdown of endogenous S5a by RNA interference techniques, the UL76 level was only minimally affected in transiently expressing cells. However, a significant reduction in the number of cells containing UL76 nuclear aggresomes was observed, which suggests that S5a may play a key role in aggresome formation. Moreover, we show that UL76 interacts with S5a in the late phase of viral infection and that knockdown of S5a hinders the development of both the replication compartment and the aggresome. In this study, we demonstrate that UL76 induces a novel nuclear aggresome, likely by subverting S5a of the UPS. Given that UL76 belongs to a conserved family, this underlying mechanism may be shared by all members of the Herpesviridae.

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Section: Discussionmentioning

confidence: 93%

Human Cytomegalovirus UL76 Elicits Novel Aggresome Formation via Interaction with S5a of the Ubiquitin Proteasome System

Lin

Jiang

Wang

et al. 2013

J Virol

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“…UL24 is an important gene that has been reported to be a virulence determinant in several alphaherpesvirinae (38,39,55,56). Based on data from previous reports, UL24 is involved in the dispersal of both nucleolin and B23, and the PD-(D/E)XK endonuclease motif of UL24 is important for this function, although nuclease activity has yet to be demonstrated (41,42,57).…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 1 UL24 Abrogates the DNA Sensing Signal Pathway by Inhibiting NF-κB Activation

Pearson

et al. 2017

J Virol

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Cyclic GMP-AMP synthase (cGAS) is a newly identified DNA sensor that recognizes foreign DNA, including the genome of herpes simplex virus 1 (HSV-1). Upon binding of viral DNA, cGAS produces cyclic GMP-AMP, which interacts with and activates stimulator of interferon genes (STING) to trigger the transcription of antiviral genes such as type I interferons (IFNs), and the production of inflammatory cytokines. HSV-1 UL24 is widely conserved among members of the herpesviruses family and is essential for efficient viral replication. In this study, we found that ectopically expressed UL24 could inhibit cGAS-STING-mediated promoter activation of IFN-␤ and interleukin-6 (IL-6), and UL24 also inhibited interferon-stimulatory DNAmediated IFN-␤ and IL-6 production during HSV-1 infection. Furthermore, UL24 selectively blocked nuclear factor B (NF-B) but not IFN-regulatory factor 3 promoter activation. Coimmunoprecipitation analysis demonstrated that UL24 bound to the endogenous NF-B subunits p65 and p50 in HSV-1-infected cells, and UL24 was also found to bind the Rel homology domains (RHDs) of these subunits. Furthermore, UL24 reduced the tumor necrosis factor alpha (TNF-␣)-mediated nuclear translocation of p65 and p50. Finally, mutational analysis revealed that the region spanning amino acids (aa) 74 to 134 of UL24 [UL24(74 -134)] is responsible for inhibiting cGAS-STING-mediated NF-B promoter activity. For the first time, UL24 was shown to play an important role in immune evasion during HSV-1 infection.IMPORTANCE NF-B is a critical component of the innate immune response and is strongly induced downstream of most pattern recognition receptors (PRRs), leading to the production of IFN-␤ as well as a number of inflammatory chemokines and interleukins. To establish persistent infection, viruses have evolved various mechanisms to counteract the host NF-B pathway. In the present study, for the first time, HSV-1 UL24 was demonstrated to inhibit the activation of NF-B in the DNA sensing signal pathway via binding to the RHDs of the NF-B subunits p65 and p50 and abolishing their nuclear translocation.KEYWORDS HSV-1, DNA sensor, UL24, NF-B, p65 T he innate immune system is the first line of defense against viral infection. The first step in innate immunity is the detection of the invading pathogen. Pathogen recognition receptors (PRRs) recognize pathogen-associated molecular patterns to trigger the production of type I interferons (IFNs) and other antiviral immune responses (1-3). Viral nucleic acids exposed in the cytoplasm are signs of foreign invasion and can be recognized by a subset of host cell PRRs. The membrane-bound Toll-like receptors recognize endosomal nucleic acids, the family of RIG-I-like receptors recognizes viral RNAs, and a broad class of putative DNA sensors recognizes viral DNA (4-6). A number of DNA sensors have been discovered in recent years, including cyclic GMP-AMP

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“…UL24-null mutants form small plaques in culture (55), and result in decreased neuronal infection as compared to wild-type virus following ocular challenge in mice (60)(61)(62). A variant in UL20 (P129L) was found to be uniquely associated with both isolates causing CNS disease in the context of disseminated infection (DISS14 and DISS29).…”

Section: Discussionmentioning

confidence: 99%

“…http://dx.doi.org/10.1101/262055 doi: bioRxiv preprint first posted online Feb. 8, 2018; these coding variations that correlate with neonatal CNS disease phenotypes impact viral proteins known to modulate cell-to-cell spread (52)(53)(54)(55)(56) and/or contribute to neurovirulence in mouse models of CNS infection (54,(57)(58)(59)(60)(61)(62)(63) (Figure 7 and Table S2), however, their role in human disease has not been described. Additional variants in proteins not known to be associated with neurovirulence were also found to be associated with neonatal CNS disease.…”

Section: Coding Variations Identified Between Neonatal Hsv-2 Isolatesmentioning

confidence: 99%

Genotypic and phenotypic diversity within the neonatal HSV-2 population

Akhtar

Bowen

Renner

et al. 2018

Preprint

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Neonates infected with herpes simplex virus (HSV) at the time of birth can have different courses of clinical disease. Approximately half of those infected display manifestations limited to the skin, eyes, or mouth (SEM disease, 45%). However, others develop invasive infections that spread systemically (disseminated, 25%) or to the central nervous system (CNS, 30%); both of which are associated with significant morbidity and mortality. The viral and/or host factors that predispose a neonate to these invasive forms of HSV infection are not known. To define the level of viral diversity within the neonatal population we evaluated ten HSV-2 isolates cultured from neonates with a range of clinical presentations. To assess viral fitness independent of host immune factors, we measured viral growth characteristics of each isolate in cultured cells. We found that HSV-2 isolates displayed diverse in vitro phenotypes. Isolates from neonates with CNS disease were associated with larger average plaque size and enhanced spread through culture, with isolates derived directly from the cerebrospinal fluid (CSF) exhibiting the most robust growth characteristics. We then sequenced the complete viral genomes of all ten neonatal HSV-2 isolates, providing the first insights into HSV genomic diversity in this clinical setting.We found extensive inter-host variation between isolates distributed throughout the HSV-2

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Differential importance of highly conserved residues in UL24 for herpes simplex virus 1 replication in vivo and reactivation

Cited by 23 publications

References 35 publications

Human Cytomegalovirus UL76 Elicits Novel Aggresome Formation via Interaction with S5a of the Ubiquitin Proteasome System

Human Cytomegalovirus UL76 Elicits Novel Aggresome Formation via Interaction with S5a of the Ubiquitin Proteasome System

Herpes Simplex Virus 1 UL24 Abrogates the DNA Sensing Signal Pathway by Inhibiting NF-κB Activation

Genotypic and phenotypic diversity within the neonatal HSV-2 population

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