Defects in Translational Regulation Mediated by the α Subunit of Eukaryotic Initiation Factor 2 Inhibit Antiviral Activity and Facilitate the Malignant Transformation of Human Fibroblasts

Perkins, Darren J.; Barber, Glen N.

doi:10.1128/mcb.24.5.2025-2040.2004

Cited by 62 publications

(50 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings are in contrast to conclusions recently derived from observations using an inducible overexpression system to produce S51A and S51D mutants of eIF2␣ (56). These studies did not detect a complete reduction in protein synthesis that would be expected with S51D eIF2␣ expression (33).…”

Section: Discussioncontrasting

confidence: 99%

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

Scheuner

Patel

Wang

et al. 2006

Journal of Biological Chemistry

124

100

View full text Add to dashboard Cite

As the molecular processes of complex cell stress signaling pathways are defined, the subsequent challenge is to elucidate how each individual event influences the final biological outcome. Phosphorylation of the translation initiation factor 2 (eIF2␣) at Ser 51 is a molecular signal that inhibits translation in response to activation of any of four diverse eIF2␣ stress kinases. We used gene targeting to replace the wild-type Ser 51 allele with an Ala in the eIF2␣ gene to test the hypothesis that translational control through eIF2␣ phosphorylation is a central death stimulus in eukaryotic cells. Homozygous eIF2␣ mutant mouse embryo fibroblasts were resistant to the apoptotic effects of dsRNA, tumor necrosis factor-␣, and serum deprivation. TNF␣ treatment induced eIF2␣ phosphorylation and activation of caspase 3 primarily through the dsRNA-activated eIF2␣ kinase PKR. In addition, expression of a phospho-mimetic Ser 51 to Asp mutant eIF2␣-activated caspase 3, indicating that eIF2␣ phosphorylation is sufficient to induce apoptosis. The proapoptotic effects of PKR-mediated eIF2␣ phosphorylation contrast with the anti-apoptotic response upon activation of the PKR-related endoplasmic reticulum eIF2␣ kinase, PERK. Therefore, divergent fates of death and survival can be mediated through phosphorylation at the same site within eIF2␣. We propose that eIF2␣ phosphorylation is fundamentally a death signal, yet it may promote either death or survival, depending upon coincident signaling events.

show abstract

Section: Discussioncontrasting

confidence: 99%

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

Scheuner

Patel

Wang

et al. 2006

Journal of Biological Chemistry

124

100

View full text Add to dashboard Cite

show abstract

“…The sensitivity of VSV translation to eIF2␣ phosphorylation is fully consistent with previous reports showing that the activation of PKR (12,27) and the subsequent phosphorylation of eIF2␣ (24,26) is an important host defense mechanism against VSV infection. These studies showed that removing PKR or keeping eIF2␣ phosphorylation from blocking eIF2 function allows enhanced VSV replication.…”

Section: Discussionsupporting

confidence: 91%

Inhibition of Host and Viral Translation during Vesicular Stomatitis Virus Infection

Connor

Lyles

2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

In cells that allow replication of vesicular stomatitis virus (VSV), there are two phases of translation inhibition: an early block of host translation and a later inhibition of viral translation. We investigated the phosphorylation of the ␣ subunit of the eIF2 complex during these two phases of viral infection. In VSV-infected cells, the accumulation of phosphorylated (inactivated) eIF2␣ did not begin until well after host protein synthesis was inhibited, suggesting that it only plays a role in blocking viral translation later after infection. Consistent with this, cells expressing an unphosphorylatable eIF2␣ showed prolonged viral protein synthesis without an effect on host protein synthesis inhibition. Induction of eIF2␣ phosphorylation at early times of viral infection by treatment with thapsigargin showed that virus and host translation are similarly inhibited, demonstrating that viral and host messages are similarly sensitive to eIF2␣ phosphorylation. A recombinant virus that expresses a mutant matrix protein and is defective in the inhibition of host and virus protein synthesis showed an altered phosphorylation of eIF2␣, demonstrating an involvement of viral protein function in inducing this antiviral response. This analysis of eIF2␣ phosphorylation, coupled with earlier findings that the eIF4F complex is modified earlier during VSV infection, supports a temporal/kinetic model of translation control, where at times soon after infection, changes in the eIF4F complex result in the inhibition of host protein synthesis; at later times, inactivation of the eIF2 complex blocks VSV protein synthesis.Many viruses can selectively inhibit host translation and still use the host translation machinery to synthesize their own proteins (for reviews, see Refs. 1-3). This provides two advantages for viral replication. It facilitates the rapid production of viral proteins, and it can also inhibit the production of host antiviral proteins (4). Both factors are important in the race of the virus against the cellular antiviral response. On the other hand, a critical part of the cellular antiviral response is the global inhibition of translation that blocks viral protein synthesis, effectively dampening virus production (5). The inhibition of both host and viral translation are apparent during infection with the prototype rhabdovirus vesicular stomatitis virus (VSV).1 During VSV infection, there is a rapid inhibition of host mRNA translation early after infection. This block of host translation is followed by a later inhibition of viral mRNA translation (6). The experiments presented here address the question of whether these two events reflect differing sensitivities of viral and host mRNAs to a single translation inhibition response or whether there are separate mechanisms controlling each inhibitory event.A substantial body of evidence implicates the phosphorylation of the initiation factor eIF2␣ as a major player in inhibiting viral translation (5). eIF2␣ is a subunit of eIF2, the multiprotein complex that is responsible ...

show abstract

“…121,122 To further clarify the role of eIF2a in apoptosis, transformation and gene regulation, our own laboratory developed inducible, murine cell lines expressing a phospho-mimetic eIF2a variant (eIF2a-S51D) and the phosphorylation-insensitive eIF2a-S51A variant. 123 Through this approach, we observed a reproducible and distinct change in the cellular morphology of both the eIF2a-S51D-and the eIF2a-S51A-expressing cell lines, for reasons that remain unclear. 124 Expression of the eIF2a-S51A variant resulted in a very mild increase in growth rates.…”

Section: Mechanisms Of Pkr Actionmentioning

confidence: 93%

“…However, cells inducibly expressing eIF2a-S51D did not undergo rapid apoptosis. 123 Thus, it appears that at least in a 3T3 L1-inducible system, the eIF2a-S51D mutant causes a modest elevation in 'background' cell death, but does not induce global cell death. Further, apoptosis in response to well-characterized stimuli such as TNFa was also unaltered by expression of either of the eIF2a variants.…”

Section: Mechanisms Of Pkr Actionmentioning

confidence: 98%

“…Further, apoptosis in response to well-characterized stimuli such as TNFa was also unaltered by expression of either of the eIF2a variants. 123 This data may indicate that while the phosphorylation of eIF2a can influence cell death, it is not sufficient on its own to induce apoptosis and perhaps requires other stress stimuli. Thus, while eIF2a has indeed been proposed to play a role in cell death, this initiation factor has also been implicated in the activation of cytoprotective gene expression pathways such as those involving NF-kB, which may actually potentially suppress apoptosis.…”

Section: Mechanisms Of Pkr Actionmentioning

confidence: 99%

See 1 more Smart Citation

The dsRNA-dependent protein kinase, PKR and cell death

Barber

2005

Cell Death Differ

View full text Add to dashboard Cite

Defects in Translational Regulation Mediated by the α Subunit of Eukaryotic Initiation Factor 2 Inhibit Antiviral Activity and Facilitate the Malignant Transformation of Human Fibroblasts

Cited by 62 publications

References 76 publications

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

Inhibition of Host and Viral Translation during Vesicular Stomatitis Virus Infection

The dsRNA-dependent protein kinase, PKR and cell death

Contact Info

Product

Resources

About