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A viral pan-end RNA element and host complex define a SARS-CoV-2 regulon

Author

Listed:
  • Debjit Khan

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Fulvia Terenzi

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • GuanQun Liu

    (Cleveland Clinic Foundation)

  • Prabar K. Ghosh

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Fengchun Ye

    (Case Western Reserve University)

  • Kien Nguyen

    (Case Western Reserve University)

  • Arnab China

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Iyappan Ramachandiran

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Shruti Chakraborty

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Jennifer Stefan

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Krishnendu Khan

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Kommireddy Vasu

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Franklin Dong

    (Lerner Research Institute, Cleveland Clinic Foundation)

  • Belinda Willard

    (Lerner Research Institute Proteomics and Metabolomics Core, Cleveland Clinic Foundation)

  • Jonathan Karn

    (Case Western Reserve University)

  • Michaela U. Gack

    (Cleveland Clinic Foundation)

  • Paul L. Fox

    (Lerner Research Institute, Cleveland Clinic Foundation)

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, generates multiple protein-coding, subgenomic RNAs (sgRNAs) from a longer genomic RNA, all bearing identical termini with poorly understood roles in regulating viral gene expression. Insulin and interferon-gamma, two host-derived, stress-related agents, and virus spike protein, induce binding of glutamyl-prolyl-tRNA synthetase (EPRS1), within an unconventional, tetra-aminoacyl-tRNA synthetase complex, to the sgRNA 3′-end thereby enhancing sgRNA expression. We identify an EPRS1-binding sarbecoviral pan-end activating RNA (SPEAR) element in the 3′-end of viral RNAs driving agonist-induction. Translation of another co-terminal 3′-end feature, ORF10, is necessary for SPEAR-mediated induction, independent of Orf10 protein expression. The SPEAR element enhances viral programmed ribosomal frameshifting, thereby expanding its functionality. By co-opting noncanonical activities of a family of essential host proteins, the virus establishes a post-transcriptional regulon stimulating global viral RNA translation. A SPEAR-targeting strategy markedly reduces SARS-CoV-2 titer, suggesting a pan-sarbecoviral therapeutic modality.

Suggested Citation

  • Debjit Khan & Fulvia Terenzi & GuanQun Liu & Prabar K. Ghosh & Fengchun Ye & Kien Nguyen & Arnab China & Iyappan Ramachandiran & Shruti Chakraborty & Jennifer Stefan & Krishnendu Khan & Kommireddy Vas, 2023. "A viral pan-end RNA element and host complex define a SARS-CoV-2 regulon," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39091-3
    DOI: 10.1038/s41467-023-39091-3
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    1. Alexey Stukalov & Virginie Girault & Vincent Grass & Ozge Karayel & Valter Bergant & Christian Urban & Darya A. Haas & Yiqi Huang & Lila Oubraham & Anqi Wang & M. Sabri Hamad & Antonio Piras & Fynn M., 2021. "Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV," Nature, Nature, vol. 594(7862), pages 246-252, June.
    2. Yaara Finkel & Orel Mizrahi & Aharon Nachshon & Shira Weingarten-Gabbay & David Morgenstern & Yfat Yahalom-Ronen & Hadas Tamir & Hagit Achdout & Dana Stein & Ofir Israeli & Adi Beth-Din & Sharon Melam, 2021. "The coding capacity of SARS-CoV-2," Nature, Nature, vol. 589(7840), pages 125-130, January.
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    1. Debjit Khan & Iyappan Ramachandiran & Kommireddy Vasu & Arnab China & Krishnendu Khan & Fabio Cumbo & Dalia Halawani & Fulvia Terenzi & Isaac Zin & Briana Long & Gregory Costain & Susan Blaser & Amand, 2024. "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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