The Herpes Simplex Virus Type 1 Regulatory Protein ICP27 Is Required for the Prevention of Apoptosis in Infected Human Cells

Aubert, Martine; Blaho, John A.

doi:10.1128/jvi.73.4.2803-2813.1999

Cited by 172 publications

(65 citation statements)

References 46 publications

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“…Since JNK is not activated at late times with the d27-1 mutant, nor are the downstream targets of p38, MNK, and MK2, we conclude that the p38 activation observed in d27-1-infected cells at 16 h postinfection is a generalized stress response, possibly induced by the onset of apoptosis. This idea is consistent with the observation that ICP27 deletion mutants induce apoptosis in other cell types (4,5,28).…”

Section: Discussionsupporting

confidence: 92%

Herpes Simplex Virus ICP27 Activation of Stress Kinases JNK and p38

Hargett¹,

McLean²,

Bachenheimer

2005

J Virol

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We previously reported that herpes simplex virus type 1 (HSV-1) can activate the stress-activated protein kinases (SAPKs) p38 and JNK. In the present study, we undertook a comprehensive and comparative analysis of the requirements for viral protein synthesis in the activation of JNK and p38. Infection with the UL36 mutant tsB7 or with UV-irradiated virus indicated that both JNK The stress-activated protein kinases (SAPKs) p38 and JNK are part of a larger family of serine/threonine terminal kinases termed mitogen-activated protein kinases (MAPK), which includes ERK1 and -2. SAPK pathways are normally activated by UV irradiation, anoxia, and engagement of proinflammatory cytokines or Fas ligand by their cognate receptors. Following ligand binding to a cognate receptor, signaling is initiated through receptor-associated kinases to a MAPKKK (MAPK kinase kinase). MAPKKKs capable of initiating the p38 or JNK pathway include MEKK1, -2, -3, and -4, ASK-1, TAK-1, and TAO. These in turn activate dual-specificity MAPK kinase kinases (MAPKKs) MKK3/6 and MKK4/7, which directly bind and phosphorylate p38 and JNK, respectively, on both tyrosine and threonine, resulting in their activation (for a review, see reference 78).All three subfamilies of human herpesviruses activate one or more of the MAPKs during infection. The betaherpesvirus cytomegalovirus activates both p38 and ERK by a mechanism dependent on viral gene expression (14,39,76) and the upstream kinases MKK3/6 and MKK1/2, respectively, (39, 40). ERK activates the early gene UL112-113 promoter (76) and phosphorylates immediate-early 86 and 72 proteins to alter their transactivation activity (40), while p38 phosphorylates retinoblastoma protein and HSP27 (39). ERK and p38 activation are required for cytomegalovirus DNA replication (16). The gammaherpesvirus Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor activates ERK and p38, causing increased vascular endothelial growth factor expression via phosphorylation of hypoxia-inducible factor 1␣ (86). The gammaherpesvirus Epstein-Barr virus activates p38 and JNK (1, 21). The immediate-early proteins BZLF1 and BRLF1 induce increased phosphorylation of p38 and JNK and activation of the ATF-2 transcription factor (1). BZLF1 expression during BRLF1-driven virus reactivation requires p38 activity (1). Among the alphaherpesviruses, HSV-2 has been reported to activate ERK through ICP10-PK binding to RAS-GAP, leading to further expression of ICP10 and prevention of apoptosis (68).Two previous reports documented the activation of the p38 and JNK (SAPK) pathways by HSV-1. Increased JNK and p38 kinase activity was observed as early as 3 hours postinfection and remained active throughout the course of infection (56,97). SAPKs were activated downstream of Ras, as infection with a dominant-negative form of Ras did not affect activation of the transcription factors ATF-2 and c-Jun, downstream targets of p38 and JNK, respectively (56). Furthermore, activation was specific for SAPKs, as ERK was not activated during infect...

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Section: Discussionsupporting

confidence: 92%

Herpes Simplex Virus ICP27 Activation of Stress Kinases JNK and p38

Hargett¹,

McLean²,

Bachenheimer

2005

J Virol

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“…2). Moreover, Vero cells might be more resistant to WNV induced apoptosis since they are known to be also more resistant to apoptosis induced by other viruses, such as herpes simplex virus (Aubert and Blaho, 1999).…”

Section: Discussionmentioning

confidence: 99%

A mouse cell-adapted NS4B mutation attenuates West Nile virus RNA synthesis

et al. 2007

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An adaptive mutation (E249G) within West Nile virus (WNV) NS4B gene was consistently recovered from replicon RNAs in C3H/He mouse cells. The E249G is located at the C-terminal tail of NS4B predicted to be on the cytoplasmic side of the endoplasmic reticulum membrane. The E249G substitution reduced replicon RNA synthesis. Compared with the wild-type NS4B, the E249G mutant protein exhibited a similar efficiency in evasion of interferon-beta response. Recombinant E249G virus exhibited smaller plaques, slower growth kinetics, and lower RNA synthesis than the wild-type virus in a host-dependent manner, with the greatest difference in rodent cells (C3H/He and BHK-21) and the least difference in mosquito cells (C3/36). Selection of revertants of E249G virus identified a second site mutation at residue 246, which could compensate for the low replication phenotype in cell culture. These results demonstrate that distinct residues within the C-terminal tail of flavivirus NS4B are critical for viral replication.

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“…While this observation suggests that ICP0 is necessary to block rRNA degradation, it does not discount the possibility that an additional viral protein(s) is also involved. It is well established by Aubert and Blaho and Zachos et al that ICP27-null-HSV infection results in many of the hallmarks associated with apoptosis through the destabilization of cellular Bcl-2 protein and a reduction in Bcl-2 RNA levels, including DNA fragmentation (1,56). However, evidence exists which illustrates that rRNA degradation is a cell type-dependent occurrence that is independent of DNA fragmentation (39).…”

Section: Discussionmentioning

confidence: 99%

ICP0 Prevents RNase L-Independent rRNA Cleavage in Herpes Simplex Virus Type 1-Infected Cells

Sobol¹,

Mossman

2006

J Virol

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The classical interferon (IFN)-dependent antiviral response to viral infection involves the regulation of IFN-stimulated genes (ISGs), one being the gene encoding cellular endoribonuclease RNase L, which arrests protein synthesis and induces apoptosis by nonspecifically cleaving rRNA. Recently, the herpes simplex virus type 1 (HSV-1) protein ICP0 has been shown to block the induction of ISGs by subverting the IFN pathway upstream of the 2-5-oligoadenylate synthetase (OAS)/RNase L pathway. We report that ICP0 also prevents rRNA degradation at late stages of HSV-1 infection, independent of its E3 ubiquitin ligase activity, and that the resultant rRNA degradation is independent of the classical RNase L antiviral pathway. Moreover, the degradation is independent of the viral RNase vhs and is independent of IFN response factor 3. These studies indicate the existence of another, previously unidentified, RNase that is part of the host antiviral response to viral infection.Viral infection of mammalian cells induces a robust antiviral response intended to restrict viral replication and propagation. A predominant characteristic of this innate immune response is the expression and secretion of interferons (IFNs), a family of immunomodulatory cytokines with antiviral and antiproliferative activities (43). Once secreted from infected cells, the type I IFNs (alpha IFN [IFN-␣] and IFN-␤) bind to their cognate class II cytokine receptors in both paracrine and autocrine fashions and induce the phosphorylation of Jak/Stat molecules, leading to the nuclear translocation of activated Stat1-Stat2-IRF9 heterotrimers. These complexes bind to the IFN-stimulated response elements (ISRE) in promoters of IFN-stimulated genes (ISGs), resulting in the robust induction of these antiviral effector molecules. Among the ISGs most intently studied are the double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), which induces protein synthesis arrest (52), and the ubiquitous 2Ј-5Ј-oligoadenylate synthetase (OAS) family of proteins, which function to promote RNA degradation (44). Once upregulated, PKR and OAS become activated by binding to dsRNA, a by-product of viral replication.OAS catalyzes the synthesis of variable short 2Ј-5Ј-linked oligoadenylates (2Ј-5ЈA) from ATP, which in turn activate the latent endoribonuclease RNase L to cleave cellular and viral RNA (36). Infection with several viruses, including vaccinia virus and encephalomyocarditis virus, leads to RNase L-dependent rRNA degradation (44). Ultimately, rRNA cleavage results in protein synthesis inhibition and apoptosis and constitutes a significant cellular antiviral event to prevent viral propagation (7). Indeed, several viruses have evolved specific mechanisms to counteract the 2Ј-5ЈA pathway, including human immunodeficiency virus type 1, vaccinia virus, and the alphaherpesvirus herpes simplex virus type 1 (HSV-1) (8, 27, 53). HSV-1 infection of conjunctival cells induces the synthesis of 2Ј-5ЈA derivatives, which antagonize RNase L activation by competing with genuine 2Ј-5ЈA...

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The Herpes Simplex Virus Type 1 Regulatory Protein ICP27 Is Required for the Prevention of Apoptosis in Infected Human Cells

Cited by 172 publications

References 46 publications

Herpes Simplex Virus ICP27 Activation of Stress Kinases JNK and p38

Herpes Simplex Virus ICP27 Activation of Stress Kinases JNK and p38

A mouse cell-adapted NS4B mutation attenuates West Nile virus RNA synthesis

ICP0 Prevents RNase L-Independent rRNA Cleavage in Herpes Simplex Virus Type 1-Infected Cells

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