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Molecular Cell
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License: Elsevier Non-Commercial
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Molecular Cell
Article . 2019 . Peer-reviewed
License: Elsevier Non-Commercial
Data sources: Crossref
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N6-Methyladenosine Modification Controls Circular RNA Immunity

Authors: Y Grace, Chen; Robert, Chen; Sadeem, Ahmad; Rohit, Verma; Sudhir Pai, Kasturi; Laura, Amaya; James P, Broughton; +5 Authors

N6-Methyladenosine Modification Controls Circular RNA Immunity

Abstract

Circular RNAs (circRNAs) are prevalent in eukaryotic cells and viral genomes. Mammalian cells possess innate immunity to detect foreign circRNAs, but the molecular basis of self versus foreign identity in circRNA immunity is unknown. Here, we show that N6-methyladenosine (m6A) RNA modification on human circRNAs inhibits innate immunity. Foreign circRNAs are potent adjuvants to induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and m6A modification abrogates immune gene activation and adjuvant activity. m6A reader YTHDF2 sequesters m6A-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not m6A-modified circRNA, directly activates RNA pattern recognition receptor RIG-I in the presence of lysine-63-linked polyubiquitin chain to cause filamentation of the adaptor protein MAVS and activation of the downstream transcription factor IRF3. CircRNA immunity has considerable parallel to prokaryotic DNA restriction modification system that transforms nucleic acid chemical modification into organismal innate immunity.

Keywords

Adenosine, Melanoma, Experimental, RNA, Circular, CD8-Positive T-Lymphocytes, Immunity, Innate, Mice, Inbred C57BL, HEK293 Cells, Lymphocytes, Tumor-Infiltrating, Adjuvants, Immunologic, Animals, DEAD Box Protein 58, Humans, Female, Immunization, Interferon Regulatory Factor-3, Interferons, Protein Multimerization, Polyubiquitin, Adaptor Proteins, Signal Transducing, HeLa Cells

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    503
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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
503
Top 0.1%
Top 1%
Top 0.1%
hybrid