RNA editing underlies genetic risk of common inflammatory diseases

Li, Qin; Gloudemans, Michael J.; Geisinger, Jonathan M.; Fan, Boming; Aguet, François; Sun, Tao; Ramaswami, Gokul; Li, Yang; Ma, Jinbiao; Pritchard, Jonathan K.; Montgomery, Stephen B.; Li, Jin Billy

doi:10.1038/s41586-022-05052-x

Cited by 89 publications

(101 citation statements)

References 85 publications

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“…To make Q-Q plots of GWAS signal annotated with edQTL associated with dsRNAs, we clumped the significant edQTLs to obtain independent signals using PLINK 87 (--clump-r2 0.4 –clump-kb 250). To control for differences in the total number between immunogenic dsRNAs and non-immunogenic dsRNAs, we randomly selected non-immunogenic dsRNAs of equal number as the immunogenic dsRNAs, which also had edQTL in the GTEx edQTL 13 . The summary statistics of GWAS were obtained as described in our recent work 13 .…”

Section: Methodsmentioning

confidence: 99%

“…To control for differences in the total number between immunogenic dsRNAs and non-immunogenic dsRNAs, we randomly selected non-immunogenic dsRNAs of equal number as the immunogenic dsRNAs, which also had edQTL in the GTEx edQTL 13 . The summary statistics of GWAS were obtained as described in our recent work 13 .…”

Section: Methodsmentioning

confidence: 99%

“…AGS can also be caused by MDA5 gain-of-function (GOF) mutations that relax the dsRNA specificity 6,37 . Recently, we uncovered the role of the ADAR1-dsRNA-MDA5 axis in common autoimmune and inflammatory diseases 13 . Genetic variants associated with dsRNA editing levels are significantly enriched in GWAS signals for immune-related diseases.…”

Section: Mainmentioning

confidence: 99%

“…Therefore, we took a different genetic approach to reveal the potential immunogenicity of the dsRNAs we identified, by taking advantage of the power of GWAS that can be very sensitive to detect weak signals with small effect sizes by using large sample sizes. We asked if immunogenic dsRNA candidates we identified would be enriched at the GWAS signals of common autoimmune and immune-related diseases, as we recently demonstrated in an independent project 13 . Indeed, we found that the immunogenic, but not the non-immunogenic dsRNA candidates, showed strong enrichment at the GWAS signals of inflammatory diseases, as exemplified in autoimmune thyroid disease, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease and others ( Fig.…”

Section: Mainmentioning

confidence: 99%

“…We validated the MDA5-dependent immunogenicity of the dsRNAs, which was dampened following ADAR1-mediated RNA editing. We anticipate that a focused analysis of immunogenic dsRNAs will greatly facilitate the understanding and treatment of cancer and inflammatory diseases in which the important roles of dsRNA editing and sensing continue to be revealed [8][9][10][11][12][13] .2…”

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confidence: 99%

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A Small Subset of Cytosolic dsRNAs Must Be Edited by ADAR1 to Evade MDA5-Mediated Autoimmunity

Sun

Geisinger

et al. 2022

Preprint

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The innate immune system detects viral infection via pattern recognition receptors and induces defense reactions such as production of type I interferon1. One such receptor, MDA5, is activated upon the recognition of double-stranded RNAs (dsRNAs) that are often produced during viral replication2. Endogenous dsRNAs evade MDA5 activation through RNA editing by ADAR1, thus preventing autoimmunity3-5. Among the large number of endogenous dsRNAs, the key substrates whose editing is critical to evade MDA5 activation (termed as immunogenic dsRNAs) remain elusive. Here we reveal the identity of human immunogenic dsRNAs, a surprisingly small fraction of all cellular dsRNAs, to fill the gap in the ADAR1-dsRNA-MDA5 axis. We found that, in contrast to previous findings6,7, the immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, an expected indication of bona fide substrates of cytosolic MDA5. The immunogenic dsRNAs, in contrast to non-immunogenic dsRNAs, tended to have shorter loop between the stems, which may facilitate dsRNA formation. They also tended to be enriched at the GWAS signals of common inflammatory diseases, implying that they are truly immunogenic. We validated the MDA5-dependent immunogenicity of the dsRNAs, which was dampened following ADAR1-mediated RNA editing. We anticipate that a focused analysis of immunogenic dsRNAs will greatly facilitate the understanding and treatment of cancer and inflammatory diseases in which the important roles of dsRNA editing and sensing continue to be revealed8-13.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

mentioning

confidence: 99%

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A Small Subset of Cytosolic dsRNAs Must Be Edited by ADAR1 to Evade MDA5-Mediated Autoimmunity

Sun

Geisinger

et al. 2022

Preprint

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Inflammatory mitochondrial nucleic acids as drivers of pathophysiology

Peace,

Hooftman,

Ryan

2023

Clinical & Translational Med

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A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

Datta,

Adamska,

Bhate

et al. 2023

WIREs RNA

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ADAR deaminases catalyze adenosine‐to‐inosine (A‐to‐I) editing on double‐stranded RNA (dsRNA) substrates that regulate an umbrella of biological processes. One of the two catalytically active ADAR enzymes, ADAR1, plays a major role in innate immune responses by suppression of RNA sensing pathways which are orchestrated through the ADAR1‐dsRNA‐MDA5 axis. Unedited immunogenic dsRNA substrates are potent ligands for the cellular sensor MDA5. Upon activation, MDA5 leads to the induction of interferons and expression of hundreds of interferon‐stimulated genes with potent antiviral activity. In this way, ADAR1 acts as a gatekeeper of the RNA sensing pathway by striking a fine balance between innate antiviral responses and prevention of autoimmunity. Reduced editing of immunogenic dsRNA by ADAR1 is strongly linked to the development of common autoimmune and inflammatory diseases. In viral infections, ADAR1 exhibits both antiviral and proviral effects. This is modulated by both editing‐dependent and editing‐independent functions, such as PKR antagonism. Several A‐to‐I RNA editing events have been identified in viruses, including in the insidious viral pathogen, SARS‐CoV‐2 which regulates viral fitness and infectivity, and could play a role in shaping viral evolution. Furthermore, ADAR1 is an attractive target for immuno‐oncology therapy. Overexpression of ADAR1 and increased dsRNA editing have been observed in several human cancers. Silencing ADAR1, especially in cancers that are refractory to immune checkpoint inhibitors, is a promising therapeutic strategy for cancer immunotherapy in conjunction with epigenetic therapy. The mechanistic understanding of dsRNA editing by ADAR1 and dsRNA sensing by MDA5 and PKR holds great potential for therapeutic applications.This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease

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RNA editing underlies genetic risk of common inflammatory diseases

Cited by 89 publications

References 85 publications

A Small Subset of Cytosolic dsRNAs Must Be Edited by ADAR1 to Evade MDA5-Mediated Autoimmunity

A Small Subset of Cytosolic dsRNAs Must Be Edited by ADAR1 to Evade MDA5-Mediated Autoimmunity

Inflammatory mitochondrial nucleic acids as drivers of pathophysiology

A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

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