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Control of alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) phosphorylation by the human

Shirin Kazemi1, Stavroula Papadopoulou, Suiyang Li

  • 1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec H3T 1E2, Canada.

Molecular and Cellular Biology
|April 3, 2004
PubMed

Insights

The human papillomavirus (HPV) E6 oncoprotein interacts with the eIF2alpha phosphorylation pathway. E6 protein can mitigate PKR-mediated apoptosis and protein synthesis inhibition during viral infections.

Area of Science:

  • Molecular Biology
  • Virology
  • Cellular Biology

Background:

  • Phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2alpha) inhibits protein synthesis during cellular stress, including viral infections.
  • The human papillomavirus (HPV) E6 oncoprotein is known to inhibit apoptosis and interferon (IFN) action, contributing to viral pathogenicity.

Purpose of the Study:

  • To investigate the functional relationship between the HPV E6 oncoprotein and eIF2alpha phosphorylation mediated by the IFN-inducible protein kinase PKR.
  • To elucidate the role of E6 in cellular responses to PKR-induced stress.

Main Methods:

  • Utilized an inducible-dimerization system to activate PKR and induce eIF2alpha phosphorylation.
  • Assessed HPV type 18 E6 protein synthesis and cellular responses to PKR activation.
  • Investigated the physical association of E6 with the GADD34/PP1 holophosphatase complex.
  • Examined the impact of E6 on eIF2alpha dephosphorylation and downstream apoptotic signaling.

Main Results:

  • HPV type 18 E6 protein synthesis was rapidly repressed upon eIF2alpha phosphorylation.
  • The E6 oncoprotein rescued cells from PKR-mediated inhibition of protein synthesis and apoptosis.
  • E6 physically associated with the GADD34/PP1 complex, facilitating eIF2alpha dephosphorylation.
  • E6 inhibited eIF2alpha-dependent transcription and translation of proapoptotic genes.

Conclusions:

  • The HPV E6 oncoprotein plays a role in modulating apoptotic signaling pathways induced by PKR and eIF2alpha phosphorylation.
  • E6's interaction with the eIF2alpha phosphorylation pathway has significant implications for HPV infection and pathogenesis.

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