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Adenovirus infection inactivates the translational inhibitors 4E-BP1 and 4E-BP2
1Department of Biochemistry and McGill Cancer Center, McGill University, Montréal, Québec, H3G 1Y6, Canada.
Abstract:
Infection with many viruses results in the selective shutoff of host protein synthesis. A common target for virus interference with host protein synthesis is the cap-binding protein complex, eIF4F. The large subunit of the complex, eIF4G, is cleaved upon picornavirus (except cardiovirus) infection. Infection with adenovirus and influenza virus causes dephosphorylation of the cap-binding subunit, eIF4E. Recently, it has been shown that infection with poliovirus or encephalomyocarditis virus activates 4E-BP1, which is a specific inhibitor of eIF4E. Here we show that early in adenovirus infection, 4E-BP1 and its related protein 4E-BP2 are phosphorylated and hence inactivated. This is not consistent with a role of 4E-BPs in adenovirus-induced shutoff, but could explain the increase in protein synthesis reported early in infection. Phosphorylation of 4E-BP1 and 4E-BP2 is consistent with earlier findings in adenovirus-infected cells on the activation of the protein kinase p70(S6k), whose phosphorylation lies on the same pathway as 4E-BPs, by E1A. Findings similar to those described here were reported for 4E-BP1 by D. Feigenblum and R. J. Schneider (1996, Mol. Cell. Biol. 16, 5450-5457).
Insights
Viruses shut down host protein synthesis by targeting the eIF4F complex. Adenovirus infection inactivates 4E-BP1 and 4E-BP2, explaining early protein synthesis increases, not shutoff.
Area of Science:
- Molecular Biology
- Virology
- Cellular Biology
Background:
- Viral infections often inhibit host protein synthesis.
- The cap-binding protein complex, eIF4F, is a frequent target for viral interference.
- Different viruses employ distinct mechanisms, including eIF4G cleavage or eIF4E dephosphorylation.
Purpose of the Study:
- To investigate the role of 4E-BP1 and 4E-BP2 in adenovirus-induced shutoff of host protein synthesis.
- To elucidate the mechanism by which adenovirus affects protein synthesis early in infection.
Main Methods:
- Analysis of 4E-BP1 and 4E-BP2 phosphorylation status in adenovirus-infected cells.
- Correlation of 4E-BP phosphorylation with known pathways, such as p70(S6k) activation by E1A.
Main Results:
- Early in adenovirus infection, 4E-BP1 and 4E-BP2 are phosphorylated and inactivated.
- This inactivation is inconsistent with a role in viral-induced shutoff.
- The observed phosphorylation aligns with the activation of p70(S6k) by the viral E1A protein.
Conclusions:
- 4E-BP1 and 4E-BP2 are not responsible for adenovirus-induced host protein synthesis shutoff.
- The phosphorylation and inactivation of 4E-BPs may explain the reported increase in protein synthesis early in adenovirus infection.