Physiologic RNA targets and refined sequence specificity of coronavirus EndoU

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. En...

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Bibliographic Details
Published in:RNA (Cambridge) 2020-12, Vol.26 (12), p.1976-1999
Main Authors: Ancar, Rachel, Li, Yize, Kindler, Eveline, Cooper, Daphne A, Ransom, Monica, Thiel, Volker, Weiss, Susan R, Hesselberth, Jay R, Barton, David J
Format: Article
Language:English
Subjects:
Animals
Bone marrow
Cells, Cultured
Coronaviruses
Double-stranded RNA
Hepatitis
Macrophages
Macrophages - virology
Mice
Mice, Inbred C57BL
Murine hepatitis virus - enzymology
Mutation
Nucleotide Motifs
Nucleotide sequence
Phosphodiesterase
Poly(A)
Polyadenylation
Protein Binding
Pyrimidines
Regulatory sequences
Ribonuclease L
RNA - chemistry
RNA - metabolism
Transcription
Uridylate-Specific Endoribonucleases - genetics
Uridylate-Specific Endoribonucleases - metabolism
Viral Nonstructural Proteins - genetics
Viral Nonstructural Proteins - metabolism
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Summary: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 U A and C A sequences (endoY A). 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 (EndoU ) or 2'-5' phosphodiesterase (PDE ) 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 U A and C A sequences (endoY A) within viral (+) strand RNA to evade dsRNA-activated host responses.
ISSN:1355-8382
1469-9001
DOI:10.1261/rna.076604.120