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PMID: 12502846 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) functions as a dominant regulator of apoptosis in hippocampal neurons involving activation of the ERK survival pathway and upregulation of the antiapoptotic protein Bag-1.

Journal of virology ·Vol. 77 ·No. 2 ·2003-01-00 ·Pages 1292-305

Perkins D, Pereira EF, Aurelian L

Abstract

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) can trigger or block apoptosis in a cell type-dependent manner. We have recently shown that the protein kinase activity of the large subunit of the HSV-2 ribonucleotide reductase (R1) protein (ICP10 PK) blocks apoptosis in cultured hippocampal neurons by activating the extracellular signal-regulated kinase (ERK) survival pathway (Perkins et al., J. Virol. 76:1435-1449, 2002). The present studies were designed to better elucidate the mechanism of ICP10 PK-induced neuroprotection and determine whether HSV-1 has similar activity. The data indicate that apoptosis inhibition by ICP10 PK involves a c-Raf-1-dependent mechanism and induction of the antiapoptotic protein Bag-1 by the activated ERK survival pathway. Also associated with neuroprotection by ICP10 PK are increased activation/stability of the transcription factor CREB and stabilization of the antiapoptotic protein Bcl-2. HSV-1 and the ICP10 PK-deleted HSV-2 mutant ICP10DeltaPK activate JNK, c-Jun, and ATF-2, induce the proapoptotic protein BAD, and trigger apoptosis in hippocampal neurons. c-Jun activation and apoptosis are inhibited in hippocampal cultures infected with HSV-1 in the presence of the JNK inhibitor SP600125, suggesting that JNK/c-Jun activation is required for HSV-1-induced apoptosis. Ectopically delivered ICP10 PK (but not its PK-negative mutant p139) inhibits apoptosis triggered by HSV-1 or ICP10DeltaPK. Collectively, the data indicate that ICP10 PK-induced activation of the ERK survival pathway results in Bag-1 upregulation and overrides the proapoptotic JNK/c-Jun signal induced by other viral proteins.

MeSH Terms
Activating Transcription Factor 2 Animals Apoptosis/physiology Carrier Proteins/physiology Caspase 3 Caspases/metabolism Chlorocebus aethiops Cyclic AMP Response Element-Binding Protein/metabolism DNA-Binding Proteins Enzyme Activation Herpesvirus 1, Human/physiology Herpesvirus 2, Human/physiology Hippocampus/cytology Mitogen-Activated Protein Kinases/metabolism Neurons/cytology Poly(ADP-ribose) Polymerases/metabolism Protein Serine-Threonine Kinases/physiology Ribonucleotide Reductases/physiology Transcription Factors/metabolism Up-Regulation/physiology Vero Cells
Chemicals
Activating Transcription Factor 2 BCL2-associated athanogene 1 protein Carrier Proteins Cyclic AMP Response Element-Binding Protein DNA-Binding Proteins Transcription Factors ICP10 protein, herpes simplex virus type 2 Ribonucleotide Reductases Poly(ADP-ribose) Polymerases Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinases CASP3 protein, human Caspase 3 Caspases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Perkins D
Departments of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201, USA.
Pereira E F R
Aurelian L
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.77.2.1292-1305.2003
Published
2003-01-00
Pages
1292-305
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC140789
Subset
IM
Grants
NIAMS NIH HHS · R01 AR042647 · United States
NINDS NIH HHS · R01 NS025296 · United States
NIAMS NIH HHS · AR42647 · United States
NINDS NIH HHS · NS25296 · United States
External Links
PubMed source DOI: 10.1128/jvi.77.2.1292-1305.2003 PMC Full Text View journal details
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