Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors.
Animals
Antiviral Agents
/ pharmacology
Cell Line
Chlorocebus aethiops
Coronavirus
/ enzymology
Coronavirus Infections
/ immunology
Endoribonucleases
/ genetics
Host Microbial Interactions
/ physiology
Humans
Interferons
/ pharmacology
Poly U
/ chemistry
RNA, Viral
/ genetics
Uridine
/ chemistry
Vero Cells
Viral Nonstructural Proteins
/ genetics
Virus Replication
/ physiology
EndoU
coronavirus
endoribonuclease
interferon
nsp15
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
07 04 2020
07 04 2020
Historique:
pubmed:
22
3
2020
medline:
23
6
2020
entrez:
22
3
2020
Statut:
ppublish
Résumé
Coronaviruses (CoVs) are positive-sense RNA viruses that can emerge from endemic reservoirs and infect zoonotically, causing significant morbidity and mortality. CoVs encode an endoribonuclease designated EndoU that facilitates evasion of host pattern recognition receptor MDA5, but the target of EndoU activity was not known. Here, we report that EndoU cleaves the 5'-polyuridines from negative-sense viral RNA, termed PUN RNA, which is the product of polyA-templated RNA synthesis. Using a virus containing an EndoU catalytic-inactive mutation, we detected a higher abundance of PUN RNA in the cytoplasm compared to wild-type-infected cells. Furthermore, we found that transfecting PUN RNA into cells stimulates a robust, MDA5-dependent interferon response, and that removal of the polyuridine extension on the RNA dampens the response. Overall, the results of this study reveal the PUN RNA to be a CoV MDA5-dependent pathogen-associated molecular pattern (PAMP). We also establish a mechanism for EndoU activity to cleave and limit the accumulation of this PAMP. Since EndoU activity is highly conserved in all CoVs, inhibiting this activity may serve as an approach for therapeutic interventions against existing and emerging CoV infections.
Identifiants
pubmed: 32198201
pii: 1921485117
doi: 10.1073/pnas.1921485117
pmc: PMC7149396
doi:
Substances chimiques
Antiviral Agents
0
RNA, Viral
0
Viral Nonstructural Proteins
0
Poly U
27416-86-0
Interferons
9008-11-1
Endoribonucleases
EC 3.1.-
nidoviral uridylate-specific endoribonuclease
EC 3.1.-
Uridine
WHI7HQ7H85
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8094-8103Subventions
Organisme : NIAID NIH HHS
ID : R01 AI085089
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007508
Pays : United States
Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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