Physiologic RNA targets and refined sequence specificity of coronavirus EndoU

Author:

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

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.

Funder

Public Health Service grants from the National Institutes of Health

the Swiss National Science Foundation

Publisher

Cold Spring Harbor Laboratory

Subject

Molecular Biology

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