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Irina S Abaeva1, Yani Arhab1, Anna Miścicka1

  • 1Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.

Biorxiv : the Preprint Server for Biology
|June 9, 2023
PubMed
Summary
This summary is machine-generated.

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SARS-CoV-2 nonstructural protein 1 (Nsp1) cleaves host mRNAs, inhibiting protein synthesis. This study reveals Nsp1 utilizes ribosomal components, not cellular enzymes, for this critical step in viral pathogenesis.

Area of Science:

  • Molecular Biology
  • Virology
  • Biochemistry

Background:

  • SARS-CoV-2 nonstructural protein 1 (Nsp1) is a key virulence factor.
  • Nsp1 inhibits host cell translation through mRNA cleavage.
  • The precise mechanism of Nsp1-mediated mRNA cleavage remains incompletely understood.

Approach:

  • Reconstituted Nsp1-mediated mRNA cleavage in vitro using various mRNA types (β-globin, EMCV IRES, CrPV IRES).
  • Investigated the requirement for canonical translation components, including 40S ribosomal subunits and initiation factors.
  • Utilized mutational analysis to identify critical residues on Nsp1 and eIF3g involved in cleavage.

Key Points:

  • Nsp1-induced mRNA cleavage occurs via ribosomal machinery, not a separate cellular endonuclease.
Keywords:
40S ribosomal subunitSARS CoV-2 Nsp1eIF3geukaryotic translation initiationmRNA cleavage

Related Experiment Videos

  • Cleavage requires Nsp1 and canonical translational components, with specific initiation factor needs varying by mRNA.
  • A minimal system for cleavage involves 40S subunits and eIF3g's RRM domain.
  • The cleavage site is on the solvent side of the 40S subunit, 18 nucleotides downstream from mRNA entry.
  • Specific surfaces on Nsp1's N-terminal domain and eIF3g's RRM domain are essential for cleavage.

    • Conclusions:

    • Nsp1 hijacks the host ribosome for mRNA cleavage, a general mechanism independent of mRNA initiation pathway.
    • Identified essential interaction sites on Nsp1 and eIF3g, providing mechanistic insights into viral translation inhibition.