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.

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.

Related Concept Videos

Leaky Scanning02:28

Leaky Scanning

During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.3K
Initiation of Translation02:33

Initiation of Translation

Initiating translation is complex because it involves multiple molecules. Initiator tRNA, ribosomal subunits, and eukaryotic initiation factors (eIFs) are all required to assemble on the initiation codon of mRNA. This process consists of several steps that are mediated by different eIFs.
First, the initiator tRNA must be selected from the pool of elongator tRNAs by eukaryotic initiation factor 2 (eIF2). The initiator tRNA (Met-tRNAi) has conserved sequence elements including modified bases at...
35.2K
Regulated mRNA Transport02:22

Regulated mRNA Transport

In eukaryotes, transcription and translation are compartmentalized; an mRNA is first synthesized in the nucleus and then selectively transported to the cytoplasm for protein synthesis. Before transport, a pre-mRNA undergoes several steps of post-transcriptional modifications including splicing, 5' capping, and the addition of a poly-adenine tail. Various proteins bind to the pre-mRNA during these modifications. The mRNA transport takes place with the help of multiple proteins playing...
6.5K
Translational Regulation01:29

Translational Regulation

Translational regulation in prokaryotes ensures efficient protein synthesis by controlling ribosome access to mRNA. This regulation is mediated by secondary RNA structures, including translational riboswitches, RNA thermometers, and small RNAs (sRNAs), which respond to intracellular and environmental signals to modulate gene expression.Translational RiboswitchesRiboswitches in the leader region of mRNAs can regulate translation by altering the accessibility of the Shine-Dalgarno (SD) sequence,...
238
Improving Translational Accuracy02:07

Improving Translational Accuracy

Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...
12.0K