Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation
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Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNAs because of its limited filament formation on imperfect duplexes, AGS variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNAs. Moreover, we identified an unexpected role of an RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context dependence of self versus non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 in recognizing dsRNA comes at a cost of self-recognition and implicates a unique role of Alu-dsRNAs as virus-like elements that shape the primate immune system.
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Major sources of dsRNA, inverted Alu repeats, are normally deaminated by ADAR to reduce their double-stranded character; decreased processing can be sensed by MDA5, resulting in IFN-I activation.
“Major sources of dsRNA, inverted Alu repeats, are normally deaminated by ADAR to reduce their double-stranded character; decreased processing can be sensed by MDA5, resulting in IFN-I activation50, 51, 98.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [98]
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Trimmomatic: a flexible trimmer for Illumina sequence data
Bolger, A. M., Lohse, M., & Usadel, B. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu170 · Cited by 65,548 · see citing works
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · see citing works
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587 · see citing works
Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration
Thorvaldsdottir, H., Robinson, J. T., & Mesirov, J. P. (2013) · Briefings in Bioinformatics · doi:10.1093/bib/bbs017 · Cited by 9,049 · see citing works
Automated generation of heuristics for biological sequence comparison
Slater, G., & Birney, E. (2005) · BMC Bioinformatics · doi:10.1186/1471-2105-6-31 · Cited by 2,902 · see citing works
RSeQC: quality control of RNA-seq experiments
Wang, L., Wang, S., & Li, W. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts356 · Cited by 2,813 · see citing works
Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L. M., Snyder, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.011 · Cited by 2,022 · see citing works
Roulois, D., Loo Yau, H., Singhania, R., Wang, Y., Danesh, A., Shen, S. Y., Han, H., Liang, G., Jones, P. A., Pugh, T. J., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.056 · Cited by 1,527 · see citing works
Functions and Regulation of RNA Editing by ADAR Deaminases
Nishikura, K. (2010) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060208-105251 · Cited by 1,303 · see citing works
Hou, F., Sun, L., Zheng, H., Skaug, B. A., Jiang, Q., & Chen, Z. J. (2011) · Cell · doi:10.1016/j.cell.2011.06.041 · Cited by 1,274 · see citing works
RNA Editing by Adenosine Deaminases That Act on RNA
Bass, B. (2002) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.71.110601.135501 · Cited by 1,272 · see citing works
Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes
Watanabe, T., Totoki, Y., Toyoda, A., Kaneda, M., Kuramochi‐Miyagawa, S., Obata, Y., Chiba, H., Kohara, Y., Kono, T., Nakano, T., et al. (2008) · Nature · doi:10.1038/nature06908 · Cited by 1,115 · see citing works
RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself
Liddicoat, B., Piskol, R., Chalk, A. M., Ramaswami, G., Higuchi, M., Hartner, J. C., Li, J. B., Seeburg, P. H., & Walkley, C. R. (2015) · Science · doi:10.1126/science.aac7049 · Cited by 963 · see citing works
Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature
Rice, G. I., Kasher, P. R., Forte, G. M. A., Mannion, N. M., Greenwood, S. M., Szynkiewicz, M., Dickerson, J. E., Bhaskar, S. S., Zampini, M., Briggs, T. A., et al. (2012) · Nature Genetics · doi:10.1038/ng.2414 · Cited by 923 · see citing works
Widespread A-to-I RNA Editing of Alu-Containing mRNAs in the Human Transcriptome
Athanasiadis, A., Rich, A. S., & Maas, S. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020391 · Cited by 743 · see citing works
Negative staining and image classification — powerful tools in modern electron microscopy
Ohi, M. D., Li, Y., Cheng, Y., & Walz, T. (2004) · Biological Procedures Online · doi:10.1251/bpo70 · Cited by 685 · see citing works
The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA
Mannion, N., Greenwood, S. M., Young, R., Cox, S. L., Brindle, J., Read, D. F., Nellåker, C., Vesely, C., Ponting, C. P., McLaughlin, P. J., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.041 · Cited by 644 · see citing works
DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration
Kaneko, H., Dridi, S., Tarallo, V., Gelfand, B. D., Fowler, B. J., Cho, W. G., Kleinman, M. E., Ponicsan, S. L., Hauswirth, W. W., Chiodo, V. A., et al. (2011) · Nature · doi:10.1038/nature09830 · Cited by 601 · see citing works
DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome
Aktaş, T., Ilik, İ., Maticzka, D., Bhardwaj, V., Rodrigues, C. P., Mittler, G., Manke, T., Backofen, R., & Akhtar, A. (2017) · Nature · doi:10.1038/nature21715 · Cited by 594 · see citing works
Rice, G., Duany, Y. D. T., Jenkinson, E. M., Forte, G. M. A., Anderson, B., Ariaudo, G., Bader‐Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., et al. (2014) · Nature Genetics · doi:10.1038/ng.2933 · Cited by 593 · see citing works
Self-citationStructural Basis for dsRNA Recognition, Filament Formation, and Antiviral Signal Activation by MDA5
Wu, B., Peisley, A., Richards, C., Yao, H., Zeng, X., Lin, C., Feixia Chu, C., Walz, T., & Hur, S. (2012) · Cell · doi:10.1016/j.cell.2012.11.048 · Cited by 572 · see citing works
Self-citationPestal, K., Funk, C. C., Snyder, J. M., Price, N. D., Treuting, P. M., & Stetson, D. B. (2015) · Immunity · doi:10.1016/j.immuni.2015.11.001 · Cited by 516 · see citing works
Jiang, X., Kinch, L. N., Brautigam, C. A., Chen, X., Du, F., Grishin, N. V., & Chen, Z. J. (2012) · Immunity · doi:10.1016/j.immuni.2012.03.022 · Cited by 407 · see citing works
Alu element‐mediated gene silencing
Chen, L., DeCerbo, J. N., & Carmichael, G. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.94 · Cited by 330 · see citing works
Delivery of proteins into living cells by reversible membrane permeabilization with streptolysin-O
Walev, I., Bhakdi, S. C., Hofmann, F., Djonder, N., Valeva, A., Aktories, K., & Bhakdi, S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051429498 · Cited by 329 · see citing works
Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition
Peisley, A., Lin, C., Wu, B., Orme-Johnson, M., Liu, M., Walz, T., & Hur, S. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113651108 · Cited by 312 · see citing works
Self-citationhiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1
Sugimoto, Y., Vigilante, A., Darbo, É., Zirra, A., Militti, C., D’Ambrogio, A., Luscombe, N. M., & Ule, J. (2015) · Nature · doi:10.1038/nature14280 · Cited by 270 · see citing works
Iwamura, T., Yoneyama, M., Yamaguchi, K., Suhara, W., Mori, W., Shiota, K., Okabe, Y., Namiki, H., & Fujita, T. (2001) · Genes to Cells · doi:10.1046/j.1365-2443.2001.00426.x · Cited by 265 · see citing works
Autoimmune Disorders Associated with Gain of Function of the Intracellular Sensor MDA5
Funabiki, M., Kato, H., Miyachi, Y., Toki, H., Motegi, H., Inoue, M., Minowa, O., Yoshida, A., Deguchi, K., Satō, H., et al. (2014) · Immunity · doi:10.1016/j.immuni.2013.12.014 · Cited by 262 · see citing works
Bruns, A. M., Leser, G. P., Lamb, R. A., & Horvath, C. M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.07.003 · Cited by 262 · see citing works
The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression
Hung, T., Pratt, G. A., Sundararaman, B., Townsend, M. J., Chaivorapol, C., Bhangale, T., Graham, R., Ortmann, W. A., Criswell, L. A., Yeo, G. W.-M., et al. (2015) · Science · doi:10.1126/science.aac7442 · Cited by 255 · see citing works
A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome
Rutsch, F., MacDougall, M. J., Lu, C., Buers, I., Mamaeva, O. A., Nitschke, Y., Rice, G., Erlandsen, H., Kehl, H.-G., Thiele, H., et al. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.12.014 · Cited by 226 · see citing works
Aicardi-Goutières Syndrome Is Caused by IFIH1 Mutations
Oda, H., Nakagawa, K., Abe, J., Awaya, T., Funabiki, M., Hijikata, A., Nishikomori, R., Funatsuka, M., Ohshima, Y., Sugawara, Y., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.06.007 · Cited by 203 · see citing works
Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments
Peisley, A., Jo, M. H., Lin, C., Wu, B., Orme-Johnson, M., Walz, T., Hohng, S., & Hur, S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208618109 · Cited by 170 · see citing works
Self-citationLi, Y., Banerjee, S., Goldstein, S. A., Dong, B., Gaughan, C., Rath, S. P., Donovan, J., Korennykh, A. V., Silverman, R. H., & Weiss, S. R. (2017) · eLife · doi:10.7554/elife.25687 · Cited by 156 · see citing works
A biochemical landscape of A-to-I RNA editing in the human brain transcriptome
Sakurai, M., Ueda, H., Yano, T., Okada, S., Terajima, H., Mitsuyama, T., Toyoda, A., Fujiyama, A., Kawabata, H., & Suzuki, T. (2014) · Genome Research · doi:10.1101/gr.162537.113 · Cited by 150 · see citing works
Brief Report: IFIH1 Mutation Causes Systemic Lupus Erythematosus With Selective IgA Deficiency
Eyck, L. V., Somer, L. D., Pombal, D., Bornschein, S., Frans, G., Humblet‐Baron, S., Moens, L., de Zegher, F., Bossuyt, X., Wouters, C. H., et al. (2015) · Arthritis & Rheumatology · doi:10.1002/art.39110 · Cited by 129 · see citing works
PKR Transduces MDA5-Dependent Signals for Type I IFN Induction
Pham, A. M., Maria, F. G. S., Lahiri, T., Friedman, E., Marié, I. J., & Levy, D. E. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005489 · Cited by 111 · see citing works
A zinc finger directory for high-affinity DNA recognition
Jamieson, A. C., Wang, H., & Kim, S. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.23.12834 · Cited by 103 · see citing works
Preparation of Distinct Ubiquitin Chain Reagents of High Purity and Yield
Dong, K. C., Helgason, E., Yu, C., Phu, L., Arnott, D. P., Bosanac, I., Compaan, D. M., Huang, O. W., Fedorova, A. V., Kirkpatrick, D. S., et al. (2011) · Structure · doi:10.1016/j.str.2011.06.010 · Cited by 88 · see citing works
Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L., Snyder, A., et al. (2016) · Cell · doi:10.1016/j.cell.2015.10.020 · Cited by 80 · see citing works
MDA5—filament, dynamics and disease
Duany, Y. D. T., Wu, B., & Hur, S. (2015) · Current Opinion in Virology · doi:10.1016/j.coviro.2015.01.011 · Cited by 73 · see citing works
Self-citationHSV infection induces increased transcription of Alu repeated sequences by RNA polymerase III
Jang, K. L., & Latchman, D. S. (1989) · FEBS Letters · doi:10.1016/0014-5793(89)81667-9 · Cited by 59 · see citing works
Karijolich, J. J., Abernathy, E., & Glaunsinger, B. A. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005260 · Cited by 51 · see citing works
Williams, W. P., Tamburic, L., & Astell, C. R. (2004) · Virology · doi:10.1016/j.virol.2004.06.040 · Cited by 39 · see citing works
Flagged first, then by citations
1 of the 46 references couldn’t be matched to a known paper.
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RIG-I-like receptors: their regulation and roles in RNA sensing
Rehwinkel, J., & Gack, M. U. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0288-3 · Cited by 1,703 · see citing works
Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade
Ishizuka, J. J., Manguso, R. T., Cheruiyot, C. K., Bi, K., Panda, A., Iracheta-Vellve, A., Miller, B. C., Du, P. P., Yates, K. B., Dubrot, J., et al. (2019) · Nature · doi:10.1038/s41586-018-0768-9 · Cited by 697 · see citing works
A-to-I RNA editing — immune protector and transcriptome diversifier
Eisenberg, E., & Levanon, E. Y. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0006-1 · Cited by 622 · see citing works
Zheng, M., & Kanneganti, T. (2020) · Immunological Reviews · doi:10.1111/imr.12909 · Cited by 591 · see citing works
N6-Methyladenosine Modification Controls Circular RNA Immunity
Chen, Y. G., Chen, R., Ahmad, S., Verma, R., Kasturi, S. P., Amaya, L., Broughton, J. P., Kim, J., Cadena, C., Pulendran, B., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.016 · Cited by 572 · see citing works
Self-citationZ-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation
Jiao, H., Wachsmuth, L., Kumari, S., Schwarzer, R., Lin, J., Eren, R. O., Fisher, A. D., Lane, R. K., Young, G. R., Kassiotis, G., et al. (2020) · Nature · doi:10.1038/s41586-020-2129-8 · Cited by 493 · see citing works
The type I interferonopathies: 10 years on
Crow, Y. J., & Stetson, D. B. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00633-9 · Cited by 489 · see citing works
The role of retrotransposable elements in ageing and age-associated diseases
Gorbunova, V., Seluanov, A., Mita, P., McKerrow, W., Fenyö, D., Boeke, J. D., Linker, S. B., Gage, F. H., Kreiling, J. A., Petrashen, A. P., et al. (2021) · Nature · doi:10.1038/s41586-021-03542-y · Cited by 457 · see citing works
ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis
Karki, R., Sundaram, B., Sharma, B. R., Lee, S., Malireddi, R. K. S., Nguyen, L. N., Christgen, S. L., Zheng, M., Wang, Y., Samir, P., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109858 · Cited by 441 · see citing works
Chen, N., Zhao, G., Xu, Y., Lv, Z., Yin, H., Zhang, S., Song, W., Li, X., Li, L., Du, Z., et al. (2018) · Genome biology · doi:10.1186/s13059-018-1594-y · Cited by 439 · see citing works
Cellular origins of dsRNA, their recognition and consequences
Chen, Y. G., & Hur, S. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00430-1 · Cited by 430 · see citing works
Self-citationRegulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors
Onomoto, K., Onoguchi, K., & Yoneyama, M. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00602-7 · Cited by 432 · see citing works
Double-Stranded RNA Sensors and Modulators in Innate Immunity
Hur, S. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041356 · Cited by 420 · see citing works
Self-citationDNA damage and repair in age-related inflammation
Zhao, Y., Simon, M. A., Seluanov, A., & Gorbunova, V. A. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00751-y · Cited by 393 · see citing works
Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5
Brisse, M. E., & Ly, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01586 · Cited by 361 · see citing works
Regulation of cGAS- and RLR-mediated immunity to nucleic acids
Ablasser, A., & Hur, S. (2019) · Nature Immunology · doi:10.1038/s41590-019-0556-1 · Cited by 333 · see citing works
Self-citationA Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation
Dias, A. G., Sampaio, N. G., & Rehwinkel, J. (2018) · Trends in Microbiology · doi:10.1016/j.tim.2018.08.007 · Cited by 309 · see citing works
PANoptosis : Mechanisms, biology, and role in disease
Sun, X., Yang, Y., Meng, X., Li, J., Liu, X., & Liu, H. (2023) · Immunological Reviews · doi:10.1111/imr.13279 · Cited by 314 · see citing works
Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency
Mehdipour, P., Marhon, S. A., Ettayebi, I., Chakravarthy, A., Hosseini, A., Wang, Y., de Castro, F. A., Yau, H. L., Ishak, C. A., Abelson, S., et al. (2020) · Nature · doi:10.1038/s41586-020-2844-1 · Cited by 298 · see citing works
KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements
Zhang, S.-M., Cai, W. L., Liu, X., Thakral, D., Luo, J., Chan, L. H., McGeary, M. K., Song, E., Blenman, K. R. M., Micevic, G., et al. (2021) · Nature · doi:10.1038/s41586-021-03994-2 · Cited by 272 · see citing works
ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation
de Reuver, R., Verdonck, S., Dierick, E., Nemegeer, J., Hessmann, E., Ahmad, S., Jans, M., Blancke, G., Nieuwerburgh, F. V., Botzki, A., et al. (2022) · Nature · doi:10.1038/s41586-022-04974-w · Cited by 246 · see citing works
Self-citationZ-DNA and Z-RNA in human disease
Herbert, A. G. (2018) · Communications Biology · doi:10.1038/s42003-018-0237-x · Cited by 243 · see citing works
ADAR1: “Editor-in-Chief” of Cytoplasmic Innate Immunity
Lamers, M. M., van den Hoogen, B. G., & Haagmans, B. L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01763 · Cited by 224 · see citing works
ADAR1 averts fatal type I interferon induction by ZBP1
Jiao, H., Wachsmuth, L., Wolf, S., Lohmann, J., Nagata, M., Kaya, G. G., Oikonomou, N., Kondylis, V., Rogg, M., Diebold, M., et al. (2022) · Nature · doi:10.1038/s41586-022-04878-9 · Cited by 222 · see citing works
ADAR1 mutation causes ZBP1-dependent immunopathology
Hubbard, N., Ames, J. M., Maurano, M. M., Chu, L. H., Somfleth, K. Y., Gokhale, N. S., Werner, M., Snyder, J. M., Lichauco, K., Savan, R., et al. (2022) · Nature · doi:10.1038/s41586-022-04896-7 · Cited by 213 · see citing works
An origin of the immunogenicity of in vitro transcribed RNA
Mu, X., Greenwald, E., Ahmad, S., & Hur, S. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky177 · Cited by 218 · see citing works
Self-citationEndogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis
Chen, R. E., Ishak, C. A., & Carvalho, D. D. D. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0506 · Cited by 206 · see citing works
Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity
Cadena, C., Ahmad, S., Xavier, A., Willemsen, J., Park, S., Park, J. W., Oh, S.-W., Fujita, T., Hou, F., Binder, M., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.017 · Cited by 196 · see citing works
Self-citationImmune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids
Bartok, E., & Hartmann, G. (2020) · Immunity · doi:10.1016/j.immuni.2020.06.014 · Cited by 184 · see citing works
Samuel, C. E. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.tm118.004166 · Cited by 172 · see citing works
The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s
Tunbak, H., Enriquez-Gasca, R., Tie, C. H. C., Gould, P. A., Mlcochova, P., Gupta, R. K., Fernandes, L., Holt, J., van der Veen, A. G., Giampazolias, E., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19170-5 · Cited by 162 · see citing works
Cellular RNA surveillance in health and disease
Wolin, S. L., & Maquat, L. E. (2019) · Science · doi:10.1126/science.aax2957 · Cited by 157 · see citing works
Zhao, Y., Ye, X., Dunker, W., Song, Y., & Karijolich, J. J. (2018) · Nature Communications · doi:10.1038/s41467-018-07314-7 · Cited by 155 · see citing works
Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome
Rice, G. I., Meyzer, C., Bouazza, N., Hully, M., Boddaert, N., Semeraro, M., Zeef, L. A. H., Rozenberg, F., Bondet, V., Duffy, D., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmc1810983 · Cited by 153 · see citing works
ADAR RNA Modifications, the Epitranscriptome and Innate Immunity
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Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA
Paget, M., Cadena, C., Ahmad, S., Wang, H., Jordan, T. X., Kim, E., Koo, B., Lyons, S. M., Ivanov, P. V., tenOever, B. R., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.03.010 · Cited by 146 · see citing works
Self-citationDistinct and Orchestrated Functions of RNA Sensors in Innate Immunity
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The role of RNA editing enzyme ADAR1 in human disease
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Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies
Uggenti, C., Lepelley, A., & Crow, Y. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041257 · Cited by 138 · see citing works
Our Conflict with Transposable Elements and Its Implications for Human Disease
Burns, K. H. (2020) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012419-032633 · Cited by 137 · see citing works
Immunogenicity of In Vitro -Transcribed RNA
Mu, X. N., & Hur, S. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00521 · Cited by 138 · see citing works
Self-citationStructures, functions and adaptations of the human LINE-1 ORF2 protein
Baldwin, E. T., van Eeuwen, T., Hoyos, D., Zalevsky, A. O., Tchesnokov, E. P., Sánchez, R., Miller, B. D., Stefano, L. H. D., Ruiz, F. X., Hancock, M., et al. (2023) · Nature · doi:10.1038/s41586-023-06947-z · Cited by 134 · see citing works
de Reuver, R., Dierick, E., Wiernicki, B., Staes, K., Seys, L., Meester, E. D., Muyldermans, T., Botzki, A., Lambrecht, B. N., Nieuwerburgh, F. V., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109500 · Cited by 117 · see citing works
Transposable Elements: A Common Feature of Neurodevelopmental and Neurodegenerative Disorders
Jönsson, M. E., Garza, R., Johansson, P. A., & Jakobsson, J. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.05.004 · Cited by 122 · see citing works
Maurano, M. M., Snyder, J. M., Connelly, C. F., Henao‐Mejia, J., Sidrauski, C., & Stetson, D. B. (2021) · Immunity · doi:10.1016/j.immuni.2021.07.001 · Cited by 122 · see citing works
ADAR1 and ZBP1 in innate immunity, cell death, and disease
Karki, R., & Kanneganti, T. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.01.001 · Cited by 122 · see citing works
Zhao, Y., Zhou, L., Li, H., Sun, T., Wen, X., Li, X., Meng, Y., Li, Y., Liu, M., Liu, S., et al. (2020) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2020.09.040 · Cited by 120 · see citing works
Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease
Tam, O. H., Ostrow, L. W., & Hammell, M. (2019) · Mobile DNA · doi:10.1186/s13100-019-0176-1 · Cited by 118 · see citing works
Tang, Q., Rigby, R. E., Young, G. R., Hvidt, A. K., Davis, T., Tan, T. K., Bridgeman, A., Townsend, A., Kassiotis, G., & Rehwinkel, J. (2021) · Immunity · doi:10.1016/j.immuni.2021.08.011 · Cited by 118 · see citing works
ADAR1p150 prevents MDA5 and PKR activation via distinct mechanisms to avert fatal autoinflammation
Hu, S.-B., Heraud-Farlow, J. E., Sun, T., Liang, Z., Goradia, A., Taylor, S., Walkley, C. R., & Li, J. B. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.09.018 · Cited by 114 · see citing works
Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function
Rice, G., Park, S., Gavazzi, F., Adang, L. A., Ayuk, L. A., Eyck, L. V., Seabra, L., Barrea, C., Battini, R., Bélot, A., et al. (2020) · Human Mutation · doi:10.1002/humu.23975 · Cited by 113 · see citing works
Self-citationPfaller, C. K., Donohue, R. C., Nersisyan, S. A., Brodsky, L., & Cattaneo, R. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2006577 · Cited by 111 · see citing works
Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases
Okude, H., Ori, D., & Kawai, T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.625833 · Cited by 103 · see citing works
ADAR1 Editing and its Role in Cancer
Xu, L., & Öhman, M. (2018) · Genes · doi:10.3390/genes10010012 · Cited by 104 · see citing works
Decoupling expression and editing preferences of ADAR1 p150 and p110 isoforms
Sun, T., Yu, Y., Wu, X., Acevedo, A., Luo, J., Wang, J., Schneider, W. M., Hurwitz, B. S., Rosenberg, B. R., Chung, H., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2021757118 · Cited by 104 · see citing works
Treatments in Aicardi–Goutières syndrome
Crow, Y. J., Shetty, J., & Livingston, J. H. (2019) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.14268 · Cited by 103 · see citing works
Cryo-EM Structures of MDA5-dsRNA Filaments at Different Stages of ATP Hydrolysis
Yu, Q., Qu, K., & Modis, Y. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.012 · Cited by 102 · see citing works
Host-directed editing of the SARS-CoV-2 genome
Mourier, T., Sadykov, M., Carr, M. J., González, G., Hall, W. W., & Pain, A. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.10.092 · Cited by 97 · see citing works
Adenosine-to-inosine RNA editing in neurological development and disease
Yang, Y., Okada, S., & Sakurai, M. (2021) · RNA Biology · doi:10.1080/15476286.2020.1867797 · Cited by 99 · see citing works
ADAR1: from basic mechanisms to inhibitors
Rehwinkel, J., & Mehdipour, P. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2024.06.006 · Cited by 97 · see citing works
Rexach, J. E., Polioudakis, D., Yin, A., Swarup, V., Chang, T. S., Nguyen, T., Sarkar, A., Chen, L., Huang, J., Lin, L.-C., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108398 · Cited by 94 · see citing works
Sensing of transposable elements by the antiviral innate immune system
Gázquez-Gutiérrez, A., Witteveldt, J., Heras, S. R., & Macías, S. (2021) · RNA · doi:10.1261/rna.078721.121 · Cited by 92 · see citing works
The Z-nucleic acid sensor ZBP1 in health and disease
Maelfait, J., & Rehwinkel, J. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20221156 · Cited by 91 · see citing works
Kato, K., Ahmad, S., Zhu, Z., Young, J. M., Mu, X. N., Park, S., Malik, H. S., & Hur, S. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.11.047 · Cited by 90 · see citing works
Self-citationChemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration
Clapes, T., Polyzou, A., Prater, P., Sagar, Morales‐Hernández, A., Ferrarini, M. G., Kehrer, N., Lefkopoulos, S., Bergo, V., Hummel, B., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00707-9 · Cited by 90 · see citing works
Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections
Pfaller, C. K., George, C. X., & Samuel, C. E. (2021) · Annual Review of Virology · doi:10.1146/annurev-virology-091919-065320 · Cited by 89 · see citing works
The competitive landscape of the dsRNA world
Cottrell, K. A., Andrews, R. J., & Bass, B. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.11.033 · Cited by 87 · see citing works
On the origin and evolution of RNA editing in metazoans
Zhang, P., Zhu, Y., Guo, Q., Li, J., Zhan, X., Yu, H., Xie, N., Tan, H., Lundholm, N., Garcia‐Cuetos, L., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112112 · Cited by 86 · see citing works
RNA Recognition and Immunity—Innate Immune Sensing and Its Posttranscriptional Regulation Mechanisms
Uehata, T., & Takeuchi, O. (2020) · Cells · doi:10.3390/cells9071701 · Cited by 86 · see citing works
Lefkopoulos, S., Polyzou, A., Derecka, M., Bergo, V., Clapes, T., Cauchy, P., Jerez‐Longres, C., Onishi‐Seebacher, M., Yin, N., Calderón, N. M., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.10.007 · Cited by 84 · see citing works
Endogenous Double-Stranded RNA
Sadeq, S., Al-Hashimi, S., Cusack, C. M., & Werner, A. (2021) · Non-Coding RNA · doi:10.3390/ncrna7010015 · Cited by 81 · see citing works
The Immunological Conundrum of Endogenous Retroelements
Kassiotis, G. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-033341 · Cited by 79 · see citing works
Activation of endogenous retroviruses during brain development causes an inflammatory response
Jönsson, M. E., Garza, R., Sharma, Y., Petri, R., Södersten, E., Johansson, J. G., Johansson, P. A., Atacho, D. A., Pircs, K., Madsen, S., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020106423 · Cited by 80 · see citing works
RNA damage compartmentalization by DHX9 stress granules
Zhou, Y., Panhale, A., Shvedunova, M., Balan, M., Gomez-Auli, A., Holz, H., Seyfferth, J., Helmstädter, M., Kayser, S., Zhao, Y., et al. (2024) · Cell · doi:10.1016/j.cell.2024.02.028 · Cited by 83 · see citing works
L1 retrotransposition in the soma: a field jumping ahead
Faulkner, G. J., & Billon, V. (2018) · Mobile DNA · doi:10.1186/s13100-018-0128-1 · Cited by 78 · see citing works
RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain
Kim, J. I., Nakahama, T., Yamasaki, R., Cruz, P. H. C., Vongpipatana, T., Inoue, M., Kanou, N., Xing, Y., Todo, H., Shibuya, T., et al. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009516 · Cited by 75 · see citing works
Dorrity, T. J., Shin, H., Wiegand, K. A., Aruda, J., Closser, M., Jung, E., Gertie, J. A., Leone, A., Polfer, R., Culbertson, B., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.adg2979 · Cited by 75 · see citing works
Mapping the dsRNA WorldPreprint
Reich, D. P., & Bass, B. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035352 · Cited by 73 · see citing works
Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
Ochoa, E., Ramirez, P., Gonzalez, E., De Mange, J., Ray, W. J., Bieniek, K. F., & Frost, B. (2023) · Science Advances · doi:10.1126/sciadv.abq5423 · Cited by 73 · see citing works
Hardy, M., Audemard, E. O., Migneault, F., Feghaly, A., Brochu, S., Gendron, P., Boilard, É., Major, F., Dieudé, M., Hébert, M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-43591-y · Cited by 73 · see citing works
Wang, A., Kang, X., Wang, J., & Zhang, S. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109478 · Cited by 72 · see citing works
RBP–RNA interactions in the control of autoimmunity and autoinflammation
Liu, J., & Cao, X. (2023) · Cell Research · doi:10.1038/s41422-022-00752-5 · Cited by 73 · see citing works
Repetitive elements in aging and neurodegeneration
Copley, K. E., & Shorter, J. (2023) · Trends in Genetics · doi:10.1016/j.tig.2023.02.008 · Cited by 70 · see citing works
Transposable elements as new players in neurodegenerative diseases
Ravel‐Godreuil, C., Znaidi, R., Bonnifet, T., Joshi, R. L., & Fuchs, J. (2021) · FEBS Letters · doi:10.1002/1873-3468.14205 · Cited by 67 · see citing works
Ohtani, H., Ørskov, A. D., Helbo, A. S., Gillberg, L., Liu, M., Zhou, W., Ungerstedt, J. S., Hellström‐Lindberg, E., Sun, W., Liang, G., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-1696 · Cited by 67 · see citing works
Novel insights into double-stranded RNA-mediated immunopathology
de Reuver, R., & Maelfait, J. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00940-3 · Cited by 66 · see citing works
All I's on the RADAR : role of ADAR in gene regulation
Shevchenko, G., & Morris, K. V. (2018) · FEBS Letters · doi:10.1002/1873-3468.13093 · Cited by 67 · see citing works
The Dichotomous Responses Driven by β-Defensins
Shelley, J. R., Davidson, D. J., & Dorin, J. R. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01176 · Cited by 65 · see citing works
STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges
Yang, K., Tang, Z., Xing, C., & Yan, N. (2023) · Neuron · doi:10.1016/j.neuron.2023.10.014 · Cited by 63 · see citing works
The Editor’s I on Disease Development
Jain, M. K., Jantsch, M. F., & Licht, K. (2019) · Trends in Genetics · doi:10.1016/j.tig.2019.09.004 · Cited by 61 · see citing works
Reactivation of Endogenous Retroelements in Cancer Development and Therapy
Ishak, C. A., & Carvalho, D. D. D. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033525 · Cited by 58 · see citing works
Choi, H., Kwon, J., Cho, M. S., Sun, Y., Zheng, X., Wang, J., Bouker, K. B., Casey, J. L., Atkins, M. B., Toretsky, J. A., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3790 · Cited by 58 · see citing works
An Update on Autoinflammatory Diseases: Interferonopathies
Davidson, S., Steiner, A., Harapas, C. R., & Masters, S. L. (2018) · Current Rheumatology Reports · doi:10.1007/s11926-018-0748-y · Cited by 59 · see citing works
TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes
LaRocca, T. J., Mariani, A., Watkins, L. R., & Link, C. D. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104514 · Cited by 56 · see citing works
Song, B., Chen, Y., Liu, X., Yuan, F., Tan, E. Y. J., Lei, Y., Song, N., Han, Y., Pascal, B. D., Griffin, P. R., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.09.008 · Cited by 55 · see citing works
The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms
Kleinová, R., Rajendra, V., Leuchtenberger, A. F., Giudice, C. L., Vesely, C., Kapoor, U., Andrea Tanzer, A., Derdak, S. V., Picardi, E., & Jantsch, M. F. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad265 · Cited by 55 · see citing works
Stok, J. E., Oosenbrug, T., ter Haar, L. R., Gravekamp, D., Bromley, C. P., Zelenay, S., Sousa, C. R. E., & van der Veen, A. G. (2022) · The EMBO Journal · doi:10.15252/embj.2021109760 · Cited by 53 · see citing works
Erdmann, E. A., Mahapatra, A., Mukherjee, P., Yang, B., & Hundley, H. A. (2020) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2020.1856768 · Cited by 52 · see citing works
Adenosine-to-inosine RNA editing in the immune system: friend or foe?
Nakahama, T., & Kawahara, Y. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03466-2 · Cited by 52 · see citing works
ALU non-B-DNA conformations, flipons, binary codes and evolution
Herbert, A. G. (2020) · Royal Society Open Science · doi:10.1098/rsos.200222 · Cited by 52 · see citing works
- Authors
- Ahmad, S., Mu, X., Yang, F., Greenwald, E., Park, J. W., Jacob, E., Zhang, C.-Z., & Hur, S.
- Affiliations
- Boston Children's Hospital (US)
- Boston College (US)
- Broad Institute (US)
- Corresponding author
- Hur, Sun
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 172
- Issue
- 4
- Pages
- 797-810.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5807104
- OpenAlex
- W2784999778
- Cited by
- 449
- References
- 46
- Citations by year
- 2026: 58 · 2025: 54 · 2024: 45 · 2023: 44 · 2022: 43 · 2021: 85 · 2020: 49 · 2019: 38 · 2018: 33
- FWCI
- 22.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research Institute
- Burroughs Wellcome Fund
- National Institutes of Health (R01AI106912, R21AI130791, R01AI111784)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- MDA5, Aicardi-Goutières syndrome, double-stranded RNA, self-tolerance, RNA duplex structure
- MeSH terms
- A549 Cells, Interferon-Induced Helicase, IFIH1, THP-1 Cells, Humans, Inflammation, Muramidase, Nervous System Malformations, Peptide Fragments, RNA, Double-Stranded, Self Tolerance, Alu Elements, Autoimmune Diseases of the Nervous System, Protein Multimerization
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