N6-Methyladenosine Modification Controls Circular RNA Immunity

Mol Cell. 2019 Oct 3;76(1):96-109.e9. doi: 10.1016/j.molcel.2019.07.016. Epub 2019 Aug 29.

Authors

Affiliations

¹ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA.
² Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
⁴ Institute for Immunity, Transplantation and Infection, Department of Pathology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
⁵ Emory Vaccine Center/Yerkes National Primate Research Center at Emory University, Atlanta, GA, USA.
⁶ Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
⁷ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: howchang@stanford.edu.

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: N6-methyladenosine; RIG-I; YTHDF; cancer immunotherapy; circular RNA; self/non-self; vaccine.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / immunology
Adaptor Proteins, Signal Transducing / metabolism
Adenosine / administration & dosage
Adenosine / analogs & derivatives*
Adenosine / immunology
Adenosine / metabolism
Adjuvants, Immunologic / administration & dosage
Animals
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
DEAD Box Protein 58 / immunology
DEAD Box Protein 58 / metabolism
Female
HEK293 Cells
HeLa Cells
Humans
Immunity, Innate*
Immunization
Interferon Regulatory Factor-3 / immunology
Interferon Regulatory Factor-3 / metabolism
Interferons / immunology
Interferons / metabolism
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Melanoma, Experimental / immunology
Melanoma, Experimental / metabolism
Melanoma, Experimental / pathology
Melanoma, Experimental / therapy*
Mice, Inbred C57BL
Polyubiquitin / immunology
Polyubiquitin / metabolism
Protein Multimerization
RNA, Circular / administration & dosage
RNA, Circular / immunology*
RNA, Circular / metabolism
RNA-Binding Proteins / immunology
RNA-Binding Proteins / metabolism
Receptors, Immunologic
Ubiquitination

Substances

Adaptor Proteins, Signal Transducing
Adjuvants, Immunologic
IRF3 protein, human
Interferon Regulatory Factor-3
MAVS protein, human
RNA, Circular
RNA-Binding Proteins
Receptors, Immunologic
YTHDF2 protein, human
Polyubiquitin
Interferons
N-methyladenosine
RIGI protein, human
Ddx58 protein, mouse
DEAD Box Protein 58
Adenosine

Abstract

Publication types

MeSH terms

Substances

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