scholarly journals The role of host eIF2α in viral infection

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Yuanzhi Liu ◽  
Mingshu Wang ◽  
Anchun Cheng ◽  
Qiao Yang ◽  
Ying Wu ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Viral Infection ◽  
Infection Process ◽  
Host Protein ◽  
Main Body ◽  
Protein Kinase R ◽  
Viral Protein Synthesis ◽  
Eif2α Phosphorylation

Abstract Background eIF2α is a regulatory node that controls protein synthesis initiation by its phosphorylation or dephosphorylation. General control nonderepressible-2 (GCN2), protein kinase R-like endoplasmic reticulum kinase (PERK), double-stranded RNA (dsRNA)-dependent protein kinase (PKR) and heme-regulated inhibitor (HRI) are four kinases that regulate eIF2α phosphorylation. Main body In the viral infection process, dsRNA or viral proteins produced by viral proliferation activate different eIF2α kinases, resulting in eIF2α phosphorylation, which hinders ternary tRNAMet-GTP-eIF2 complex formation and inhibits host or viral protein synthesis. The stalled messenger ribonucleoprotein (mRNP) complex aggregates under viral infection stress to form stress granules (SGs), which encapsulate viral RNA and transcription- and translation-related proteins, thereby limiting virus proliferation. However, many viruses have evolved a corresponding escape mechanism to synthesize their own proteins in the event of host protein synthesis shutdown and SG formation caused by eIF2α phosphorylation, and viruses can block the cell replication cycle through the PERK-eIF2α pathway, providing a favorable environment for their own replication. Subsequently, viruses can induce host cell autophagy or apoptosis through the eIF2α-ATF4-CHOP pathway. Conclusions This review summarizes the role of eIF2α in viral infection to provide a reference for studying the interactions between viruses and hosts.

scholarly journals Human Cytomegalovirus pTRS1 and pIRS1 Antagonize Protein Kinase R To Facilitate Virus Replication

2016 ◽  
Vol 90 (8) ◽  
pp. 3839-3848 ◽  
Author(s):  
Benjamin Ziehr ◽  
Heather A. Vincent ◽  
Nathaniel J. Moorman
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Viral Protein ◽  
Hcmv Infection ◽  
Initiation Factor ◽  
Host Defenses ◽  
Protein Kinase R ◽  
Viral Protein Synthesis ◽  
Eif2α Phosphorylation ◽  
Hcmv Replication

ABSTRACTHuman cytomegalovirus (HCMV) counteracts host defenses that otherwise act to limit viral protein synthesis. One such defense is the antiviral kinase protein kinase R (PKR), which inactivates the eukaryotic initiation factor 2 (eIF2) translation initiation factor upon binding to viral double-stranded RNAs. Previously, the viral TRS1 and IRS1 proteins were found to antagonize the antiviral kinase PKR outside the context of HCMV infection, and the expression of either pTRS1 or pIRS1 was shown to be necessary for HCMV replication. In this study, we found that expression of either pTRS1 or pIRS1 is necessary to prevent PKR activation during HCMV infection and that antagonism of PKR is critical for efficient viral replication. Consistent with a previous study, we observed decreased overall levels of protein synthesis, reduced viral protein expression, and diminished virus replication in the absence of both pTRS1 and pIRS1. In addition, both PKR and eIF2α were phosphorylated during infection when pTRS1 and pIRS1 were absent. We also found that expression of pTRS1 was both necessary and sufficient to prevent stress granule formation in response to eIF2α phosphorylation. Depletion of PKR prevented eIF2α phosphorylation, rescued HCMV replication and protein synthesis, and reversed the accumulation of stress granules in infected cells. Infection with an HCMV mutant lacking the pTRS1 PKR binding domain resulted in PKR activation, suggesting that pTRS1 inhibits PKR through a direct interaction. Together our results show that antagonism of PKR by HCMV pTRS1 and pIRS1 is critical for viral protein expression and efficient HCMV replication.IMPORTANCETo successfully replicate, viruses must counteract host defenses that limit viral protein synthesis. We have identified inhibition of the antiviral kinase PKR by the viral proteins TRS1 and IRS1 and shown that this is a critical step in HCMV replication. Our results suggest that inhibiting pTRS1 and pIRS1 function or restoring PKR activity during infection may be a successful strategy to limit HCMV disease.

scholarly journals Protein Kinase R Is Responsible for the Phosphorylation of eIF2α in Rotavirus Infection

2010 ◽  
Vol 84 (20) ◽  
pp. 10457-10466 ◽  
Author(s):  
Margarito Rojas ◽  
Carlos F. Arias ◽  
Susana López
Keyword(s):  
Protein Synthesis ◽  
Kinase Domain ◽  
Cell Protein ◽  
Protein Kinase R ◽  
Viral Protein Synthesis ◽  
Α Subunit ◽  
Rotavirus Infection ◽  
Eif2α Phosphorylation ◽  
Infected Cells ◽  
Interferon System

ABSTRACT The eukaryotic initiation translation factor 2 (eIF2) represents a key point in the regulation of protein synthesis. This factor delivers the initiator Met-tRNA to the ribosome, a process that is conserved in all eukaryotic cells. Many types of stress reduce global translation by triggering the phosphorylation of the α subunit of eIF2, which reduces the formation of the preinitiation translation complexes. Early during rotavirus infection, eIF2α becomes phosphorylated, and even under these conditions viral protein synthesis is not affected, while most of the cell protein synthesis is blocked. Here, we found that the kinase responsible for the phosphorylation of eIF2α in rotavirus-infected cells is PKR, since in mouse embryonic fibroblasts deficient in the kinase domain of PKR, or in MA104 cells where the expression of PKR was knocked down by RNA interference, eIF2α was not phosphorylated upon rotavirus infection. The viral component responsible for the activation of PKR seems to be viral double-stranded RNA, which is found in the cytoplasm of infected cells, outside viroplasms. Taken together, these results suggest that rotaviruses induce the PKR branch of the interferon system and have evolved a mechanism to translate its proteins, surpassing the block imposed by eIF2α phosphorylation.

scholarly journals GADD34-mediated dephosphorylation of eIF2α facilitates pseudorabies virus replication by maintaining de novo protein synthesis

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Ting Zhu ◽  
Xueli Jiang ◽  
Hangkuo Xin ◽  
Xiaohui Zheng ◽  
Xiaonuan Xue ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Pseudorabies Virus ◽  
De Novo ◽  
Initiation Factor ◽  
Protein Kinase R ◽  
Eif2α Phosphorylation ◽  
Phosphorylation Level ◽  
Global Protein Synthesis ◽  
De Novo Protein Synthesis

AbstractViruses have evolved multiple strategies to manipulate their host’s translational machinery for the synthesis of viral proteins. A common viral target is the alpha subunit of eukaryotic initiation factor 2 (eIF2α). In this study, we show that global protein synthesis was increased but the eIF2α phosphorylation level was markedly decreased in porcine kidney 15 (PK15) cells infected with pseudorabies virus (PRV), a swine herpesvirus. An increase in the eIF2α phosphorylation level by salubrinal treatment or transfection of constructs expressing wild-type eIF2α or an eIF2α phosphomimetic [eIF2α(S51D)] attenuated global protein synthesis and suppressed PRV replication. To explore the mechanism involved in the inhibition of eIF2α phosphorylation during PRV infection, we examined the phosphorylation status of protein kinase R-like endoplasmic reticulum kinase (PERK) and double-stranded RNA-dependent protein kinase R (PKR), two kinases that regulate eIF2α phosphorylation during infection with numerous viruses. We found that the level of neither phosphorylated (p)-PERK nor p-PKR was altered in PRV-infected cells or the lungs of infected mice. However, the expression of growth arrest and DNA damage-inducible protein 34 (GADD34), which promotes eIF2α dephosphorylation by recruiting protein phosphatase 1 (PP1), was significantly induced both in vivo and in vitro. Knockdown of GADD34 and inhibition of PP1 activity by okadaic acid treatment led to increased eIF2α phosphorylation but significantly suppressed global protein synthesis and inhibited PRV replication. Collectively, these results demonstrated that PRV induces GADD34 expression to promote eIF2α dephosphorylation, thereby maintaining de novo protein synthesis and facilitating viral replication.

scholarly journals Hepatic stellate cell proliferation: A potential role of protein kinase R

Hepatology ◽  
2011 ◽  
Vol 54 (4) ◽  
pp. 1484-1485 ◽  
Author(s):  
Sara Ceccarelli ◽  
Nadia Panera ◽  
Anna Alisi ◽  
Valerio Nobili
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Hepatic Stellate Cell ◽  
Potential Role ◽  
Stellate Cell ◽  
Protein Kinase R

scholarly journals The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

2021 ◽  
Vol 13 ◽  
Author(s):  
Nicolás W. Martinez ◽  
Felipe E. Gómez ◽  
Soledad Matus
Keyword(s):  
Protein Kinase ◽  
Pathological Process ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Kinase R ◽  
Eukaryotic Translation ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Initiation Factor 2

There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer’s disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR’s contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

The Role of Protein Kinase R in the Interferon Response

2011 ◽  
Vol 31 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Agnieszka Pindel ◽  
Anthony Sadler
Keyword(s):  
Protein Kinase ◽  
Interferon Response ◽  
Protein Kinase R

scholarly journals Severe Acute Respiratory Syndrome Coronavirus Triggers Apoptosis via Protein Kinase R but Is Resistant to Its Antiviral Activity

2008 ◽  
Vol 83 (5) ◽  
pp. 2298-2309 ◽  
Author(s):  
Verena Krähling ◽  
David A. Stein ◽  
Martin Spiegel ◽  
Friedemann Weber ◽  
Elke Mühlberger
Keyword(s):  
Protein Kinase ◽  
Severe Acute Respiratory Syndrome ◽  
Chromatin Condensation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Kinase R ◽  
Beta Interferon ◽  
Reverse Transcription Pcr ◽  
Eif2α Phosphorylation

ABSTRACT In this study, infection of 293/ACE2 cells with severe acute respiratory syndrome coronavirus (SARS-CoV) activated several apoptosis-associated events, namely, cleavage of caspase-3, caspase-8, and poly(ADP-ribose) polymerase 1 (PARP), and chromatin condensation and the phosphorylation and hence inactivation of the eukaryotic translation initiation factor 2α (eIF2α). In addition, two of the three cellular eIF2α kinases known to be virus induced, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), were activated by SARS-CoV. The third kinase, general control nonderepressible-2 kinase (GCN2), was not activated, but late in infection the level of GCN2 protein was significantly reduced. Reverse transcription-PCR analyses revealed that the reduction of GCN2 protein was not due to decreased transcription or stability of GCN2 mRNA. The specific reduction of PKR protein expression by antisense peptide-conjugated phosphorodiamidate morpholino oligomers strongly reduced cleavage of PARP in infected cells. Surprisingly, the knockdown of PKR neither enhanced SARS-CoV replication nor abrogated SARS-CoV-induced eIF2α phosphorylation. Pretreatment of cells with beta interferon prior to SARS-CoV infection led to a significant decrease in PERK activation, eIF2α phosphorylation, and SARS-CoV replication. The various effects of beta interferon treatment were found to function independently on the expression of PKR. Our results show that SARS-CoV infection activates PKR and PERK, leading to sustained eIF2α phosphorylation. However, virus replication was not impaired by these events, suggesting that SARS-CoV possesses a mechanism to overcome the inhibitory effects of phosphorylated eIF2α on viral mRNA translation. Furthermore, our data suggest that viral activation of PKR can lead to apoptosis via a pathway that is independent of eIF2α phosphorylation.

scholarly journals Stress-Activated Protein Kinase Pathway Functions To Support Protein Synthesis and Translational Adaptation in Response to Environmental Stress in Fission Yeast

2005 ◽  
Vol 4 (11) ◽  
pp. 1785-1793 ◽  
Author(s):  
Isabelle Dunand-Sauthier ◽  
Carol A. Walker ◽  
Jana Narasimhan ◽  
Amanda K. Pearce ◽  
Ronald C. Wek ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Osmotic Stress ◽  
Environmental Stress ◽  
Fission Yeast ◽  
Translation Initiation ◽  
Mitogen Activated Protein Kinase ◽  
Wild Type ◽  
Eif2α Phosphorylation ◽  
Mitogen Activated Protein

ABSTRACT The stress-activated protein kinase (SAPK) pathway plays a central role in coordinating gene expression in response to diverse environmental stress stimuli. We examined the role of this pathway in the translational response to stress in Schizosaccharomyces pombe. Exposing wild-type cells to osmotic stress (KCl) resulted in a rapid but transient reduction in protein synthesis. Protein synthesis was further reduced in mutants disrupting the SAPK pathway, including the mitogen-activated protein kinase Wis1 or the mitogen-activated protein kinase Spc1/Sty1, suggesting a role for these stress response factors in this translational control. Further polysome analyses revealed a role for Spc1 in supporting translation initiation during osmotic stress, and additionally in facilitating translational adaptation. Exposure to oxidative stress (H2O2) resulted in a striking reduction in translation initiation in wild-type cells, which was further reduced in spc1 − cells. Reduced translation initiation correlated with phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) in wild-type cells. Disruption of Wis1 or Spc1 kinase or the downstream bZip transcription factors Atf1 and Pap1 resulted in a marked increase in eIF2α phosphorylation which was dependent on the eIF2α kinases Hri2 and Gcn2. These findings suggest a role for the SAPK pathway in supporting translation initiation and facilitating adaptation to environmental stress in part through reducing eIF2α phosphorylation in fission yeast.

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