Control of α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein

Implications for eIF2α-Dependent Gene Expression and Cell Death

Shirin Kazemi, Stavroula Papadopoulou, Suiyang Li, Qiaozhu Su, Shuo Wang, Akihiko Yoshimura, Greg Matlashewski, Thomas E. Dever, Antonis E. Koromilas

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine 51 inhibits protein synthesis in cells subjected to various forms of stress including virus infection. The human papillomavirus (HPV) E6 oncoprotein contributes to virus-induced pathogenicity through multiple mechanisms including the inhibition of apoptosis and the blockade of interferon (IFN) action. We have investigated a possible functional relationship between the E6 oncoprotein and eIF2α phosphorylation by an inducible-dimerization form of the IFN-inducible protein kinase PKR. Herein, we demonstrate that HPV type 18 E6 protein synthesis is rapidly repressed upon eIF2α phosphorylation caused by the conditional activation of the kinase. The remainder of E6, however, can rescue cells from PKR-mediated inhibition of protein synthesis and induction of apoptosis. E6 physically associates with GADD34/PP1 holophosphatase complex, which mediates translational recovery, and facilitates eIF2α dephosphorylation. Inhibition of eIF2α phosphorylation by E6 mitigates eIF2α-dependent responses to transcription and translation of proapoptotic genes. These findings demonstrate, for the first time, a role of the oncogenic E6 in apoptotic signaling induced by PKR and eIF2α phosphorylation. The functional interaction between E6 and the eIF2α phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.

Original languageEnglish (US)
Pages (from-to)3415-3429
Number of pages15
JournalMolecular and cellular biology
Volume24
Issue number8
DOIs
StatePublished - Apr 1 2004

Fingerprint

Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factors
Human papillomavirus 18
Oncogene Proteins
Cell Death
Phosphorylation
Gene Expression
Interferons
eIF-2 Kinase
Apoptosis
Papillomavirus Infections
Dimerization
Virus Diseases
Serine
Virulence
Proteins
Phosphotransferases
Viruses

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Control of α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein : Implications for eIF2α-Dependent Gene Expression and Cell Death. / Kazemi, Shirin; Papadopoulou, Stavroula; Li, Suiyang; Su, Qiaozhu; Wang, Shuo; Yoshimura, Akihiko; Matlashewski, Greg; Dever, Thomas E.; Koromilas, Antonis E.

In: Molecular and cellular biology, Vol. 24, No. 8, 01.04.2004, p. 3415-3429.

Research output: Contribution to journalArticle

Kazemi, Shirin ; Papadopoulou, Stavroula ; Li, Suiyang ; Su, Qiaozhu ; Wang, Shuo ; Yoshimura, Akihiko ; Matlashewski, Greg ; Dever, Thomas E. ; Koromilas, Antonis E. / Control of α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein : Implications for eIF2α-Dependent Gene Expression and Cell Death. In: Molecular and cellular biology. 2004 ; Vol. 24, No. 8. pp. 3415-3429.
@article{b2aa440ddee946fcaed166e3d040ff8f,
title = "Control of α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein: Implications for eIF2α-Dependent Gene Expression and Cell Death",
abstract = "Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine 51 inhibits protein synthesis in cells subjected to various forms of stress including virus infection. The human papillomavirus (HPV) E6 oncoprotein contributes to virus-induced pathogenicity through multiple mechanisms including the inhibition of apoptosis and the blockade of interferon (IFN) action. We have investigated a possible functional relationship between the E6 oncoprotein and eIF2α phosphorylation by an inducible-dimerization form of the IFN-inducible protein kinase PKR. Herein, we demonstrate that HPV type 18 E6 protein synthesis is rapidly repressed upon eIF2α phosphorylation caused by the conditional activation of the kinase. The remainder of E6, however, can rescue cells from PKR-mediated inhibition of protein synthesis and induction of apoptosis. E6 physically associates with GADD34/PP1 holophosphatase complex, which mediates translational recovery, and facilitates eIF2α dephosphorylation. Inhibition of eIF2α phosphorylation by E6 mitigates eIF2α-dependent responses to transcription and translation of proapoptotic genes. These findings demonstrate, for the first time, a role of the oncogenic E6 in apoptotic signaling induced by PKR and eIF2α phosphorylation. The functional interaction between E6 and the eIF2α phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.",
author = "Shirin Kazemi and Stavroula Papadopoulou and Suiyang Li and Qiaozhu Su and Shuo Wang and Akihiko Yoshimura and Greg Matlashewski and Dever, {Thomas E.} and Koromilas, {Antonis E.}",
year = "2004",
month = "4",
day = "1",
doi = "10.1128/MCB.24.8.3415-3429.2004",
language = "English (US)",
volume = "24",
pages = "3415--3429",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "8",

}

TY - JOUR

T1 - Control of α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein

T2 - Implications for eIF2α-Dependent Gene Expression and Cell Death

AU - Kazemi, Shirin

AU - Papadopoulou, Stavroula

AU - Li, Suiyang

AU - Su, Qiaozhu

AU - Wang, Shuo

AU - Yoshimura, Akihiko

AU - Matlashewski, Greg

AU - Dever, Thomas E.

AU - Koromilas, Antonis E.

PY - 2004/4/1

Y1 - 2004/4/1

N2 - Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine 51 inhibits protein synthesis in cells subjected to various forms of stress including virus infection. The human papillomavirus (HPV) E6 oncoprotein contributes to virus-induced pathogenicity through multiple mechanisms including the inhibition of apoptosis and the blockade of interferon (IFN) action. We have investigated a possible functional relationship between the E6 oncoprotein and eIF2α phosphorylation by an inducible-dimerization form of the IFN-inducible protein kinase PKR. Herein, we demonstrate that HPV type 18 E6 protein synthesis is rapidly repressed upon eIF2α phosphorylation caused by the conditional activation of the kinase. The remainder of E6, however, can rescue cells from PKR-mediated inhibition of protein synthesis and induction of apoptosis. E6 physically associates with GADD34/PP1 holophosphatase complex, which mediates translational recovery, and facilitates eIF2α dephosphorylation. Inhibition of eIF2α phosphorylation by E6 mitigates eIF2α-dependent responses to transcription and translation of proapoptotic genes. These findings demonstrate, for the first time, a role of the oncogenic E6 in apoptotic signaling induced by PKR and eIF2α phosphorylation. The functional interaction between E6 and the eIF2α phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.

AB - Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine 51 inhibits protein synthesis in cells subjected to various forms of stress including virus infection. The human papillomavirus (HPV) E6 oncoprotein contributes to virus-induced pathogenicity through multiple mechanisms including the inhibition of apoptosis and the blockade of interferon (IFN) action. We have investigated a possible functional relationship between the E6 oncoprotein and eIF2α phosphorylation by an inducible-dimerization form of the IFN-inducible protein kinase PKR. Herein, we demonstrate that HPV type 18 E6 protein synthesis is rapidly repressed upon eIF2α phosphorylation caused by the conditional activation of the kinase. The remainder of E6, however, can rescue cells from PKR-mediated inhibition of protein synthesis and induction of apoptosis. E6 physically associates with GADD34/PP1 holophosphatase complex, which mediates translational recovery, and facilitates eIF2α dephosphorylation. Inhibition of eIF2α phosphorylation by E6 mitigates eIF2α-dependent responses to transcription and translation of proapoptotic genes. These findings demonstrate, for the first time, a role of the oncogenic E6 in apoptotic signaling induced by PKR and eIF2α phosphorylation. The functional interaction between E6 and the eIF2α phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=1842505312&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1842505312&partnerID=8YFLogxK

U2 - 10.1128/MCB.24.8.3415-3429.2004

DO - 10.1128/MCB.24.8.3415-3429.2004

M3 - Article

VL - 24

SP - 3415

EP - 3429

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 8

ER -