Citation: Snider DL, Horner SM (2021) The RNA modification of an RNA modifier prevents self-RNA recognition. PLoS Biol 19 (7): e3001342. https://doi.org/10.1371/journal.pbio.3001342

Released: July 30, 2021

Copyright ©: © 2021 Snider, Horner. This is an open access article distributed under the terms of the Creative Commons Attribution License, which allows unrestricted use, distribution, and reproduction in any medium, provided that the original author and source are acknowledged.

Financing: The authors did not receive any specific funding for this work.

Competing interests: The authors have stated that there are no competing interests.

Abbreviations:
ADAR1, adenosine deaminase that acts on RNA 1; AGS, Aicardi-Goutières syndrome; A-to-I, adenosine-to-inosine; dsRNA, double stranded RNA; IFN, interferon; MDA5, Melanoma Differentiation – Associated Protein 5; m6thA, N6-methyladenosine; PRR, pattern recognition receptor; RIG, retinoic acid inducible gene I; ssRNA, single-stranded RNA; YTHDF1, YTH N6 methyladenosine RNA binding protein 1

The distinction between self and foreign nucleic acids, for example from viruses, is crucial to enable the induction of type I interferon (IFN) and at the same time to prevent auto-inflammation. IFN is induced when cytosolic RNA pattern recognition receptors (PRRs), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) are specific patterns in RNA that are commonly found in viruses as not themselves or perceive strange. The RNA patterns that mark mRNA as foreign include the lack of a 7-methylguanosine cap, the lack of 2’O-methylation at the first nucleotide, or double-stranded RNA (dsRNA) structures. Proper mRNA capping and conversion of dsRNA into single-stranded RNA (ssRNA) are therefore necessary so that the self-mRNA escapes immune detection. The cellular RNA deaminase adenosine deaminase, which acts on RNA 1 (ADAR1), catalyzes the conversion of adenosine to inosine (A-to-I) in dsRNA structures, resulting in ssRNA that is largely immune to immune perception [1] . While cellular mRNA is typically not double-stranded, dsRNA can arise in cellular mRNA that contains specific repetitive elements. These elements include Alu retro elements that contain repetitive sequences found primarily in introns and the 3 ‘untranslated regions of the mRNA. Alu repeats are base paired, resulting in a dsRNA structure that is a potent activator of PRRs. Therefore, the A-to-I editing activity of ADAR1 is essential for IFN induction by immunostimulatory dsRNA. to prevent [2] . Indeed, the autoimmune disease Aicardi-Goutières syndrome (AGS) is linked to mutations in genes that encode dsRNA-sensing or processing proteins, such as the dsRNA sensor MDA5 and the cellular RNA deaminase ADAR1 [3] .

Recently, the RNA modification N6-methyladenosine (m6thA) was found to be another RNA pattern that marks RNA as self. m6thA can protect mRNA from detection by RIG-I, a mechanism co-opted by RNA viruses to evade immune surveillance [4] . The function of m6thA on viral RNA is not limited to immune evasion and can have both positive and negative effects on viral infections, either due to direct effects on viral RNA or indirect effects on cellular mRNAs, which encode factors important for the immune response [4,5] . For example m6thOne on IFNB1, which codes for the cytokine IFN-β, reduces its mRNA half-life and m6thA on antiviral mRNAs can affect their expression by increasing translation or decreasing stability. Thus, modifications to RNA, including m6thA and A-to-I editing can play important and diverse roles in viral infection and the innate immune response of the host. Even so, the full interplay of how these and other RNA modifications orchestrate antiviral signaling remains unclear.

In a new study published in PLOS biology, Terajima and colleagues try to find the intersection of m. to understand6thA and A-to-I processing with glioblastoma cells as a model [6] . Previous studies identified a preserved m6thA website in ADAR1 Transcript and an inverse relationship between m6thA and A-to-I processing, suggesting a causal relationship between m6thA modification on ADAR1 and A-to-I processing could exist. This new work shows that the m6thAn RNA-binding protein called YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1), which does the translation of m. promotes6thA-containing mRNAs, binds both isoforms of ADAR1 to varying degrees, with a strong enrichment for the IFN-induced p150 isoform and a lower enrichment for the basally expressed p110 isoform was observed (1). In contrast to the previously described inverse relationship between m6thA and A-to-I editing was the expression of the IFN-induced ADAR1-p150 protein after the depletion of either the m6thA scribe enzyme METTL3 or METTL14 or the m6thA-binding protein YTHDF1. This indicates that m6thA deposit and its recognition by YTHDF1 are important for the translation of the ADAR1p150 isoform. As a result, this led to a global reduction in A-to-I editing events of the cellular mRNA, which led to increased cellular dsRNA levels and subsequent detection by the dsRNA sensor MDA5 for the induction of IFN. These results support the work of others and indicate that MDA5 is activated by self-RNA in ADAR1 deficiency [2,7,8] . Thus, during the IFN response, the m6thThe A-binding protein YTHDF1 increases ADAR1-p150 expression in glioblastoma cells to facilitate A-to-I editing of self-RNA and to prevent the activation of dsRNA sensors.

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Fig. 1. YTHDF1 promotes the translation of m6thA-modified, IFN-induced ADAR1 to prevent immune activation by self-RNA.

(1) IFN signaling, which induces dsRNA, (2) activates transcription of IFN-stimulated genes, including m6thA-modified ADAR1 p150. Left: (3) The m6thOne reader, YTHDF1, is promoting the translation of ADAR1 p150, (4) which then catalyzes A-to-I editing of dsRNA, (5) converts it to ssRNA. Right: (3) In the absence of YTHDF1 ADAR1 The translation of p150 is attenuated, (4) resulting in reduced editing and accumulation of dsRNA, (5) which activates the dsRNA sensor MDA5 to induce IFN. ADAR1, adenosine deaminase that acts on RNA 1; A-to-I, adenosine-to-inosine; dsRNA, double stranded RNA; IFN, interferon; MDA5, Melanoma Differentiation – Associated Protein 5; m6thA, N6-methyladenosine; ssRNA, single stranded RNA; YTHDF1, YTH N6 methyladenosine RNA binding protein 1.

https://doi.org/10.1371/journal.pbio.3001342.g001

This study by Terajima and colleagues expands our understanding of how RNA modifications can directly control gene expression and indirectly regulate innate immune system signaling, all of which could contribute to autoimmune diseases, so the field has much to consider for future studies. For example, the depletion of YTHDF1 resulted in increased dsRNA and IFN induction, suggesting that m6thA and its regulatory proteins could play an important role in preventing autoinflammation. Interestingly, this regulation was unique to glioblastoma cells in the cell types tested, as other cell types did not induce IFN in response to YTHDF1 depletion, suggesting that this may be a mechanism that is shared in human cells of glial origin. Since other studies on YTHDF1 in an RNA virus infection have not shown that the loss of its expression leads to a broad induction of IFN. leads [4] , there are likely important mechanisms that explain these cell type differences. Examining the breadth of this phenomenon in different cell types will expand our understanding of how these differences are controlled.

Interestingly, the source of the dsRNA produced by glioblastoma cells in response to IFN treatment is also unknown. IFN does not globally change the abundance of Alu elements, a common source of dsRNA [7,8] although more dsRNA is produced in glioblastoma cells in response to IFN [6] . It therefore remains to be clarified whether certain classes of mRNAs with secondary structure are induced by IFN and then edited by ADAR1 p150, as they occur in response to bacterial lipopolysaccharide, or whether there are RNA processing defects that induce more dsRNA independent of Alu repeats as seen by others [9,10] . In addition, it remains unknown whether IFN induces dsRNA in other cell types and how the cell normally dissolves this dsRNA to prevent detection by dsRNA sensors. Ultimately, the work of Terajima and colleagues created a platform to define the interplay between RNA modifications and gene expression and how these can affect cellular homeostasis and infection. In addition, it contributes to the growing body of work that reveals the complex mechanisms of cellular surveillance that distinguish foreign or dysregulated nucleic acids from their own nucleic acids.

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