Physiologic RNA targets and refined sequence specificity of coronavirus EndoU

Rachel Ancar, Yize Li, Eveline Kindler, Daphne A. Cooper, Monica Ransom, Volker Thiel, Susan R. Weiss, Jay R. Hesselberth, David J. Barton

Research output: Contribution to journalArticlepeer-review

Abstract

Coronavirus EndoU inhibits dsRNA-activated antiviral responses; however, the physiologic RNA substrates of EndoU are unknown. In this study, we used mouse hepatitis virus (MHV)-infected bone marrow–derived macrophage (BMM) and cyclic phosphate cDNA sequencing to identify the RNA targets of EndoU. EndoU targeted viral RNA, cleaving the 3′′ side of pyrimidines with a strong preference for UA and CA sequences (endoYA). EndoU-dependent cleavage was detected in every region of MHV RNA, from the 5′′ NTR to the 3′′ NTR, including transcriptional regulatory sequences (TRS). Cleavage at two CA dinucleotides immediately adjacent to the MHV poly(A) tail suggests a mechanism to suppress negative-strand RNA synthesis and the accumulation of viral dsRNA. MHV with EndoU (EndoUmut) or 2′′–5′′ phosphodiesterase (PDEmut) mutations provoked the activation of RNase L in BMM, with corresponding cleavage of RNAs by RNase L. The physiologic targets of EndoU are viral RNA templates required for negative-strand RNA synthesis and dsRNA accumulation. Coronavirus EndoU cleaves UA and CA sequences (endoYA) within viral (+) strand RNA to evade dsRNA-activated host responses.

Original languageEnglish (US)
Pages (from-to)1976-1999
Number of pages24
JournalRNA
Volume26
Issue number12
DOIs
StatePublished - Dec 2020
Externally publishedYes

Keywords

  • Coronavirus
  • DsRNA
  • Endoribonuclease
  • Innate immunity
  • Mouse hepatitis virus

ASJC Scopus subject areas

  • Molecular Biology

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