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PABP1 Drives the Selective Translation of Influenza A Virus mRNA
Cyrus M de Rozières1, Alberto Pequeno1, Shandy Shahabi1
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0314, USA.
Abstract:
Influenza A virus (IAV) is a human-infecting pathogen with a history of causing seasonal epidemics and on several occasions worldwide pandemics. Infection by IAV causes a dramatic decrease in host mRNA translation, whereas viral mRNAs are efficiently translated. The IAV mRNAs have a highly conserved 5'-untranslated region (5'UTR) that is rich in adenosine residues. We show that the human polyadenylate binding protein 1 (PABP1) binds to the 5'UTR of the viral mRNAs. The interaction of PABP1 with the viral 5'UTR makes the translation of viral mRNAs more resistant to canonical cap-dependent translation inhibition than model mRNAs. Additionally, PABP1 bound to the viral 5'UTR can recruit eIF4G in an eIF4E-independent manner. These results indicate that PABP1 bound to the viral 5'UTR may promote eIF4E-independent translation initiation.
Insights
Influenza A virus (IAV) evades host defenses by hijacking the human polyadenylate binding protein 1 (PABP1). This interaction enhances viral mRNA translation, promoting IAV replication during infection.
Area of Science:
- Virology
- Molecular Biology
- Biochemistry
Background:
- Influenza A virus (IAV) causes significant global health burdens through seasonal epidemics and pandemics.
- IAV infection inhibits host mRNA translation while efficiently translating its own viral mRNAs.
- IAV mRNAs possess a conserved 5'-untranslated region (5'UTR) rich in adenosine residues.
Purpose of the Study:
- To investigate the mechanism by which IAV achieves efficient translation during host shutoff.
- To determine the role of the IAV 5'UTR in viral mRNA translation.
- To identify host factors interacting with the IAV 5'UTR and their functional consequences.
Main Methods:
- Biochemical assays to detect binding of human polyadenylate binding protein 1 (PABP1) to the IAV 5'UTR.
- Translation assays comparing viral and model mRNAs in the presence of PABP1.
- Investigating the recruitment of translation initiation factors (eIF4G, eIF4E) by PABP1-bound viral 5'UTR.
Main Results:
- Human PABP1 binds specifically to the adenosine-rich 5'UTR of IAV mRNAs.
- PABP1 binding confers resistance to cap-dependent translation inhibition on viral mRNAs.
- PABP1 facilitates eIF4G recruitment to viral mRNAs in an eIF4E-independent manner.
Conclusions:
- PABP1 interaction with the IAV 5'UTR is a key mechanism for efficient viral translation.
- This interaction promotes cap-independent translation initiation, bypassing host shutoff.
- Targeting the PABP1-IAV 5'UTR interaction could be a strategy for antiviral development.
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