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We performed a genome-wide CRISPR screen and showed that GGNBP2, CNOT10, and CNOT11 interact and regulate sensing of unedited cellular dsRNA. We found that GGNBP2 acts between dsRNA transcription and its cytoplasmic sensing by MDA5. GGNBP2 loss prevented induction of type I IFN and autoinflammation after the loss of ADAR1 editing activity by modifying the subcellular distribution of endogenous A-to-I editing substrates and reducing cytoplasmic dsRNA load. These findings reveal previously undescribed pathways to modify diseases associated with\n            <jats:italic>ADAR<\/jats:italic>\n            mutations and may be determinants of response or resistance to small-molecule ADAR1 inhibitors.\n          <\/jats:p>","DOI":"10.1126\/sciimmunol.adk0412","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T19:03:32Z","timestamp":1732302212000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":12,"title":["GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3786-8474","authenticated-orcid":true,"given":"Jacki E.","family":"Heraud-Farlow","sequence":"first","affiliation":[{"name":"St. Vincent\u2019s Institute of Medical Research, Fitzroy, VIC 3065, Australia."},{"name":"Department of Medicine, St. Vincent\u2019s Hospital, Melbourne Medical School, University of Melbourne, Fitzroy, VIC 3065, Australia."},{"name":"Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia."},{"name":"Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott R.","family":"Taylor","sequence":"additional","affiliation":[{"name":"St. Vincent\u2019s Institute of Medical Research, Fitzroy, VIC 3065, Australia."},{"name":"Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9630-6236","authenticated-orcid":true,"given":"Alistair M.","family":"Chalk","sequence":"additional","affiliation":[{"name":"St. Vincent\u2019s Institute of Medical Research, Fitzroy, VIC 3065, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3655-8893","authenticated-orcid":true,"given":"Adriana","family":"Escudero","sequence":"additional","affiliation":[{"name":"Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela (USC) - 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