ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation

Reuver, Richard de; Verdonck, Simon; Dierick, Evelien; Nemegeer, Josephine; Hessmann, Eline; Ahmad, Sadeem; Jans, Maude; Blancke, Gillian; Nieuwerburgh, Filip Van; Botzki, Alexander; Vereecke, Lars; Loo, Geert; Declercq, Wim; Hur, Sun; Vandenabeele, Peter; Maelfait, Jonathan

doi:10.1038/s41586-022-04974-w

Cited by 123 publications

(105 citation statements)

References 61 publications

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“…2e). Our finding appears to contradict with findings that suggest the importance of Zα domain of ADAR1 in human patients 35,46 and animal models [47][48][49][50][51][52][53][54] . The discrepancy may suggest that overexpression of p150 in our cellular assays compensate the effect of the Zα domain.…”

Section: Cytoplasmic Editing Is Required To Suppress Isg Inductioncontrasting

confidence: 99%

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: Cytoplasmic Editing Is Required To Suppress Isg Inductioncontrasting

confidence: 99%

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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“…Deletion of ADAR1 or mutant of the Zα domain of ADAR1 causes the accumulation of ERV-derived dsRNA and spontaneous activation of ZBP1 [ 160 , 161 ]. The abnormal activation of ZBP1 causes embryonic lethality, intestinal cell death and skin inflammation similar to RIPK1 −/− or RIPK1 mR/mR mice [ 162 , 163 ]. ZBP1 plays a dual role in mice with impaired ADAR1 function.…”

Section: Zbp1 Signaling In Auto-inflammatory Diseasesmentioning

confidence: 99%

“…ZBP1 plays a dual role in mice with impaired ADAR1 function. On the one hand, ZBP1 induces RIPK3-mediated necroptosis and CASP-8-mediated apoptosis which is MAVS-independent [ 162 , 163 ]. On the other hand, ZBP1 promotes the RIPK1- and RIPK3-independent, but MAVS-dependent IFN-I responses and stimulates interferonopathies [ 160 ].…”

Section: Zbp1 Signaling In Auto-inflammatory Diseasesmentioning

confidence: 99%

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

Hao

Yang

et al. 2022

IJMS

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Z-conformation nucleic acid binding protein 1 (ZBP1), a powerful innate immune sensor, has been identified as the important signaling initiation factor in innate immune response and the multiple inflammatory cell death known as PANoptosis. The initiation of ZBP1 signaling requires recognition of left-handed double-helix Z-nucleic acid (includes Z-DNA and Z-RNA) and subsequent signaling transduction depends on the interaction between ZBP1 and its adapter proteins, such as TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), and RIPK3. ZBP1 activated innate immunity, including type-I interferon (IFN-I) response and NF-κB signaling, constitutes an important line of defense against pathogenic infection. In addition, ZBP1-mediated PANoptosis is a double-edged sword in anti-infection, auto-inflammatory diseases, and tumor immunity. ZBP1-mediated PANoptosis is beneficial for eliminating infected cells and tumor cells, but abnormal or excessive PANoptosis can lead to a strong inflammatory response that is harmful to the host. Thus, pathogens and host have each developed multiplex tactics targeting ZBP1 signaling to maintain strong virulence or immune homeostasis. In this paper, we reviewed the mechanisms of ZBP1 signaling, the effects of ZBP1 signaling on host immunity and pathogen infection, and various antagonistic strategies of host and pathogen against ZBP1. We also discuss existent gaps regarding ZBP1 signaling and forecast potential directions for future research.

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“…Similarly, the keyword “modulation” has also appeared in the past 2 years. Recently, there have been many high-quality reports on the regulation of necroptosis, including those on the interaction between adenosine deaminase acting on RNA 1 (ADAR1) and ZBP1 ( de Reuver et al, 2022 ; Hubbard et al, 2022 ; Jiao et al, 2022 ) and the complex protein network of necroptosis ( Horne et al, 2022 ). These results are consistent with our keyword analysis.…”

Section: Discussionmentioning

confidence: 99%

Bibliometric analysis of publications on necroptosis from 2001 to 2021

Liu

Zhou

Wang

et al. 2022

Front. Cell Dev. Biol.

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Background: Necroptosis plays an important role in inflammation, cancer, and neurodegenerative diseases. In recent years, the number of studies related to necroptosis has increased and research has become increasingly in-depth. This study aimed to summarize the research conducted since 2001 to discover hotspots and trends in the field of necroptosis.Methods: The Web of Science Core database was used to identify global publications on necroptosis from 2001 to 2021. Bibliometric analysis was performed using Rstudio, VOSviewer, and CiteSpace.Results: The number of publications related to necroptosis gradually increased from 2001 to 2021. Vandenabeele P had the most publications at 45. Yuan JY had the most citations at 5,901. Necroptosis research has been dominated by China and Chinese institutions. Cell Death and Disease had the highest number of related publications among the examined journals. Seven of the top 10 most cited papers had more than 500 citations. Necroptosis, cell death, autophagy, injury, cancer, activated B cell nuclear factor kappa-light chain enhancer, and oxidative stress were important keywords in keyword analysis. Recent research has increasingly focused on breast cancer, receptor-interacting serine/threonine protein kinase 1, modulation, pseudokinase mixed lineage kinase domain-like protein, membrane, protection, and cycle.Conclusion: Interest in necroptosis-related research continues to increase steadily, and there is close cooperation between countries and institutions in the field of necroptosis. The study of necroptosis-related molecules and mechanisms, and the relationship between necroptosis and cancer, may be hotspots and directions in future research.

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ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation

Cited by 123 publications

References 61 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

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

Bibliometric analysis of publications on necroptosis from 2001 to 2021

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