Role of protein kinase A and the serine-rich region of herpes simplex virus type 1 ICP4 in viral replication

Xia, Kai; Knipe, David M.; DeLuca, Neal A.

doi:10.1128/jvi.70.2.1050-1060.1996

Cited by 45 publications

(32 citation statements)

References 66 publications

(101 reference statements)

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“…In addition, the E1a, E3 and E4 promoters of Ad contain CREs (Leza and Hearing, 1989; Meyer et al ., 1993). In HSV, ICP4 is a substrate for PKA and its phosphorylation promotes HSV lytic replication (Xia et al ., 1996).…”

Section: Discussionmentioning

confidence: 99%

PKA/PrKX activity is a modulator of AAV/adenovirus interaction

Pasquale

2003

The EMBO Journal

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Interference between viruses occurs when infection by one virus results in the inhibition of replication of another virus. Adeno-associated virus (AAV2) is a human parvovirus with the unique characteristics of a dependence upon a helper virus for a productive infection and the ability to interfere with the replication of the helper virus. Previously, we demonstrated that AAV2 Rep78 and Rep52 interact and inhibit cAMP-dependent protein kinase A (PKA) and its novel homolog PrKX. We hypothesized that modulation of PKA activity by AAV2 may be responsible for inhibition of helper virus replication. In this study we demonstrate that adenovirus replication is sensitive to PKA activity and that AAV2 Rep78/Rep52 proteins contain an inhibitory domain similar to that of the heat-stable PKA inhibitor. This domain, while not directly necessary for AAV2 replication and packaging, is necessary to preserve AAV2 replication ®tness during an Ad co-infection. Furthermore, a mutant AAV2 virus lacking this region fails to inhibit adenovirus replication. Thus, inhibition of PKA activity by AAV2 constitutes a novel form of viral interference.

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Section: Discussionmentioning

confidence: 99%

PKA/PrKX activity is a modulator of AAV/adenovirus interaction

Pasquale

2003

The EMBO Journal

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“…For example, we have not tested the ability of these mutants to support the growth of an ICP27-null mutant virus in cells of neuronal origin. Recently, it has been shown that deletion of a highly conserved polyserine tract found between residues 184 and 198 in HSV-1 ICP4 results in a virus that is marginally impaired for growth in culture and in the eyes of infected mice but is completely impaired for growth in the trigeminal ganglia (2,53). To address questions on specific functions and interactions of ICP27 during viral infection, the kinase consensus site mutations are being introduced into the viral genome by marker transfer.…”

Section: Discussionmentioning

confidence: 99%

“…Little is known about which cellular kinases phosphorylate ICP27 in vivo. However, kinases such as PKA, CKII, and PKC have been implicated in HSV-1 replication (53). Furthermore, there are good consensus sites for PKA, CKII, and PKC phosphorylation in the predicted peptide sequence of ICP27.…”

Section: Figmentioning

confidence: 99%

Analysis of the Phosphorylation Sites of Herpes Simplex Virus Type 1 Regulatory Protein ICP27

Zhi

Sandri‐Goldin

1999

J Virol

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The herpes simplex virus type 1 (HSV-1) regulatory protein ICP27 is a 63-kDa phosphoprotein required for viral replication. ICP27 has been shown to contain both stable phosphate groups and phosphate groups that cycle on and off during infection (K. W. Wilcox, A. Kohn, E. Sklyanskaya, and B. Roizman, J. Virol. 33:167–182, 1980). Despite extensive genetic analysis of the ICP27 gene, there is no information available about the sites of the ICP27 molecule that are phosphorylated during viral infection. In this study, we mapped several of the phosphorylation sites of ICP27 following in vivo radiolabeling. Phosphoamino acid analysis showed that serine is the only amino acid that is phosphorylated during infection. Two-dimensional phosphopeptide mapping showed a complex tryptic phosphopeptide pattern with at least four major peptides and several minor peptides. In addition, ICP27 purified from transfected cells yielded a similar phosphopeptide pattern, suggesting that cellular kinases phosphorylate ICP27 during viral infection. In vitro labeling showed that protein kinase A (PKA), PKC, and casein kinase II (CKII) were able to differentially phosphorylate ICP27, resulting in distinct phosphopeptide patterns. The major phosphorylation sites of ICP27 appeared to cluster in the N-terminal portion of the protein, such that a frameshift mutant that encodes amino acids 1 to 163 yielded a phosphopeptide pattern very similar to that seen with the wild-type protein. Further, using small deletion and point mutations in kinase consensus sites, we have elucidated individual serine residues that are phosphorylated in vivo. Specifically, the serine at residue 114 was highly phosphorylated by PKA and the serine residues at positions 16 and 18 serve as targets for CKII phosphorylation in vivo. These kinase consensus site mutants were still capable of complementing the growth of an ICP27-null mutant virus. Interestingly, phosphorylation of the serine at residue 114, which lies within the major nuclear localization signal, appeared to modulate the efficiency of nuclear import of ICP27.

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“…The goal of this study was to analyze the replication of an ICP27-null (44) recombinant HSV-1 strain (vBS⌬27) in cultured human cells. Initially, we were interested in directly comparing the cytopathic effects of the ICP27-null virus replication in human cells with that in Vero cells, since some mutant viruses, especially those carrying mutations in genes encoding IE proteins (3,42,47), were shown to have phenotypes which varied with the type of cell line or tissue used for the infections. Monolayer cultures of either Vero and Vero 2.2 (nonhuman) or 143tk Ϫ , HEp-2, and HeLa (human) cells were mock infected or infected with vBS⌬27, KOS1.1, or vBS⌬27R as described in Materials and Methods.…”

Section: Differing Morphologies Of Vbs⌬27-infected Cell Monolayersmentioning

confidence: 99%

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

Aubert

Blaho

1999

J Virol

172

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The herpes simplex virus type 1 (HSV-1) ICP27 protein is an immediate-early or α protein which is essential for the optimal expression of late genes as well as the synthesis of viral DNA in cultures of Vero cells. Our specific goal was to characterize the replication of a virus incapable of synthesizing ICP27 in cultured human cells. We found that infection with an HSV-1 ICP27 deletion virus of at least three separate strains of human cells did not produce immediate-early or late proteins at the levels observed following wild-type virus infections. Cell morphology, chromatin condensation, and genomic DNA fragmentation measurements demonstrated that the human cells died by apoptosis after infection with the ICP27 deletion virus. These features of the apoptosis were identical to those which occur during wild-type infections of human cells when total protein synthesis has been inhibited. Vero cells infected with the ICP27 deletion virus did not exhibit any of the features of apoptosis. Based on these results, we conclude that while HSV-1 infection likely induced apoptosis in all cells, viral evasion of the response differed among the cells tested in this study.

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Role of protein kinase A and the serine-rich region of herpes simplex virus type 1 ICP4 in viral replication

Cited by 45 publications

References 66 publications

PKA/PrKX activity is a modulator of AAV/adenovirus interaction

PKA/PrKX activity is a modulator of AAV/adenovirus interaction

Analysis of the Phosphorylation Sites of Herpes Simplex Virus Type 1 Regulatory Protein ICP27

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

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