Resistance of mRNA translation to acute endoplasmic reticulum stress-inducing agents in herpes simplex virus type 1-infected cells requires multiple virus-encoded functions.

TitleResistance of mRNA translation to acute endoplasmic reticulum stress-inducing agents in herpes simplex virus type 1-infected cells requires multiple virus-encoded functions.
Publication TypeJournal Article
Year of Publication2006
AuthorsMulvey M, Arias C, Mohr I
JournalJ Virol
Volume80
Issue15
Pagination7354-63
Date Published2006 Aug
ISSN0022-538X
KeywordsAnimals, Antigens, Differentiation, Antiviral Agents, Cell Cycle Proteins, Cercopithecus aethiops, eIF-2 Kinase, Endoplasmic Reticulum, Herpes Simplex, Herpesvirus 1, Human, Humans, Peptide Chain Initiation, Translational, Phosphorylation, Protein Biosynthesis, Protein Phosphatase 1, RNA, Messenger, RNA-Binding Proteins, Tunicamycin, Vero Cells, Viral Proteins, Virus Replication
Abstract

Via careful control of multiple kinases that inactivate the critical translation initiation factor eIF2 by phosphorylation of its alpha subunit, the cellular translation machinery can rapidly respond to a spectrum of environmental stresses, including viral infection. Indeed, virus replication produces a battery of stresses, such as endoplasmic reticulum (ER) stress resulting from misfolded proteins accumulating within the lumen of this organelle, which could potentially result in eIF2alpha phosphorylation and inhibit translation. While cellular translation is exquisitely sensitive to ER stress-inducing agents, protein synthesis in herpes simplex virus type 1 (HSV-1)-infected cells is notably resistant. Sustained translation in HSV-1-infected cells exposed to acute ER stress does not involve the interferon-induced, double-stranded RNA-responsive eIF2alpha kinase PKR, and it does not require either the PKR inhibitor encoded by the Us11 gene or the eIF2alpha phosphatase component specified by the gamma(1)34.5 gene, the two viral functions known to regulate eIF2alpha phosphorylation. In addition, although ER stress potently induced the GADD34 cellular eIF2alpha phosphatase subunit in uninfected cells, it did not accumulate to detectable levels in HSV-1-infected cells under identical exposure conditions. Significantly, resistance of translation to the acute ER stress observed in infected cells requires HSV-1 gene expression. Whereas blocking entry into the true late phase of the viral developmental program does not abrogate ER stress-resistant translation, the presence of viral immediate-early proteins is sufficient to establish a state permissive of continued polypeptide synthesis in the presence of ER stress-inducing agents. Thus, one or more previously uncharacterized viral functions exist to counteract the accumulation of phosphorylated eIF2alpha in response to ER stress in HSV-1-infected cells.

DOI10.1128/JVI.00479-06
Alternate JournalJ. Virol.
PubMed ID16840316
PubMed Central IDPMC1563692