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SARS-CoV-2 and MERS-CoV disrupt host protein synthesis via nsp1 with differential effects on the integrated stress

Nicholas A Parenti1,2, Renee Cusic3,4,5, David M Renner1,2

  • 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.

Biorxiv : the Preprint Server for Biology
|January 9, 2026
PubMed

Insights

Coronaviruses like SARS-CoV-2 and MERS-CoV evade host defenses by manipulating protein synthesis. Understanding these differences is key to developing new antiviral therapies against these serious public health threats.

Area of Science:

  • Virology and Molecular Biology
  • Host-Pathogen Interactions
  • Infectious Diseases

Background:

  • Coronaviruses (CoVs) pose significant global health risks, necessitating effective antiviral treatments and vaccines.
  • Understanding how CoVs, particularly SARS-CoV-2 and MERS-CoV, overcome host antiviral mechanisms is crucial for disease control.
  • The conserved non-structural protein (nsp)1 is known to inhibit host protein synthesis and degrade host mRNAs, while protecting viral RNA.

Purpose of the Study:

  • To investigate the distinct mechanisms by which SARS-CoV-2 and MERS-CoV nsp1 proteins interact with and manipulate the host integrated stress response (ISR).
  • To elucidate how nsp1 from different betacoronaviruses affects host protein synthesis, mRNA stability, and stress granule formation.
  • To identify differences in nsp1 function between SARS-CoV-2 and MERS-CoV that could inform the development of targeted antiviral strategies.

Main Methods:

  • Utilized recombinant SARS-CoV-2 and MERS-CoV expressing nsp1 mutants with alterations in conserved domains.
  • Infected wildtype (WT) and knockout (PKR KO, PERK KO) cells to assess host protein synthesis.
  • Employed single-molecule fluorescence in situ hybridization (smFISH) to analyze host mRNA degradation.
  • Monitored stress granule formation and expression of GADD34, a regulator of eIF2α phosphorylation.

Main Results:

  • SARS-CoV-2 nsp1 infection led to translation shutdown in WT and PKR KO cells, but this was rescued in PERK KO cells, suggesting PERK's role.
  • MERS-CoV nsp1 mutants rescued translation even in WT cells, indicating a different interaction with the ISR.
  • SARS-CoV-2 WT suppressed GADD34, while nsp1 mutants and MERS-CoV WT induced it.
  • Both viruses' nsp1 proteins promoted host mRNA degradation, but SARS-CoV-2 WT suppressed stress granule formation, whereas its nsp1 mutants induced them.

Conclusions:

  • SARS-CoV-2 and MERS-CoV exhibit distinct strategies in their interaction with the host ISR and nsp1-mediated control of protein synthesis.
  • Differences in nsp1 function between these lethal coronaviruses highlight the complexity of coronavirus-host interactions.
  • These findings provide critical insights for developing specific antiviral therapeutics against current and future coronavirus outbreaks.
Keywords:
Cell BiologyMajorMicrobiologyMinorcoronavirusintegrated stress responsemRNA degradationmRNA translationnonstructural protein1

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