How RNA modifications regulate the antiviral response

Abstract

Induction of the antiviral innate immune response is highly regulated at the RNA level, particularly by RNA modifications. Recent discoveries have revealed how RNA modifications play key roles in cellular surveillance of nucleic acids and in controlling gene expression in response to viral infection. These modifications have emerged as being essential for a functional antiviral response and maintaining cellular homeostasis. In this review, we will highlight these and other discoveries that describe how the antiviral response is controlled by modifications to both viral and cellular RNA, focusing on how mRNA cap modifications, N6-methyladenosine, and RNA editing all contribute to coordinating an efficient response that properly controls viral infection.

Keywords: N6-methyladenosine; RNA editing; adenosine deaminases acting on RNA; cap modification; innate immunity; interferon; pattern recognition receptors.

Figure 1.. 5′ mRNA capping regulates the antiviral response.

A) Schematic of the canonical 5′ mRNA cap structures and the enzymes involved in their processing (RNA triphosphatase (RNA TPase); RNA guanylyltransferase (GTase); guanine-N7 methyltransferase (N7 MTase); CTMR1, CMTR2, and PCIF1). B) Diagram showing roles of 5′ capping in antiviral response. Modification of incoming viral RNA can alter RIG-I binding and subsequent MAVS/TBK1 and IRF3 signaling to induce type I interferon (IFN). IFN signals to other cells via JAK/STAT and ISGF3 to induce IFN-stimulated genes (ISGs) including the cap-1 methyltransferase CMTR1 and the cap modification sensor proteins, IFIT1 and IFIT3, which inhibit viral translation.

Figure 2.. m⁶A regulates the antiviral response.

A) Schematic of adenosine (A) to N6-methyladenosine (m⁶A) modification with m⁶A machinery “writer,” “eraser,” and “reader” proteins indicated. B) Diagram showing roles of m⁶A in antiviral response. Modification of incoming viral RNA can inhibit RIG-I binding and subsequent MAVS/TBK1 and IRF3 signaling to induce type I IFN. The transcript encoding IFN-β is m⁶A-modified and subject to YTHDF2-dependent degradation. IFN signals to other cells via JAK/STAT and ISGF3 to induce transcription of ISG mRNA, which is m⁶A-modified and subject to YTHDF-dependent regulation. ISGs, such as ISG20, and possibly others, regulate m⁶A RNA.

Figure 3.. A-to-I editing regulates the antiviral response.

A) Schematic of adenosine and the known enzymes involved in its modification to inosine. B) Diagram showing roles of A-to-I editing in the antiviral response. A-to-I editing of incoming viral RNA can inhibit binding by PRRs that sense dsRNA and subsequent MAVS/TBK1/IRF3 signaling that induces type I IFN or inhibits translation. IFN signals to other cells via JAK/STAT and ISGF3 signaling induce transcription of ISGs, including ADAR1 p150. ADAR1 p150 A-to-I edits newly transcribed endogenous host dsRNA (Alu elements) to prevent detection by PRRs and aberrant IFN induction.