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Upon engagement with dsRNA derived from viral infection, MDA5 initiates coordinated signal transduction leading to type I IFN induction to restrict viral replication. In this study, we describe a targeted cleavage events of MDA5 by the 3C protease from Theilovirus. Upon ectopic expression of theilovirus 3C protease from Saffold virus or Theiler\u2019s murine encephalomyelitis virus but not encephalomyocarditis virus, fragments of cleaved MDA5 were observed in a dose-dependent manner. When enzymatically inactive Theilovirus 3C protease was expressed, MDA5 cleavage was completely abrogated. Mass spectrometric analysis identified two cleavage sites at the C terminus of MDA5, cleaving off one of the RNA-binding domains. The same cleavage pattern was observed during Theilovirus infection. The cleavage of MDA5 by Theilovirus protease impaired ATP hydrolysis, RNA binding, and filament assembly on RNA, resulting in dysfunction of MDA5 as an innate immune RNA sensor for IFN induction. Furthermore, the cleavage-resistant MDA5 mutant against the 3C protease showed an enhanced IFN response during Saffold virus infection, indicating that Theilovirus has a strategy to circumvent the antiviral immune response by cleaving MDA5 using 3C protease. In summary, these data suggest MDA5 cleavage by 3C protease as a novel immune evasive strategy of Theilovirus.<\/jats:p>","DOI":"10.4049\/jimmunol.2200565","type":"journal-article","created":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T06:47:46Z","timestamp":1672728466000},"page":"335-347","source":"Crossref","is-referenced-by-count":6,"title":["Theilovirus 3C Protease Cleaves the C-Terminal Domain of the Innate Immune RNA Sensor, Melanoma Differentiation\u2013Associated Gene 5, and Impairs Double-Stranded RNA\u2013Mediated IFN Response"],"prefix":"10.1093","volume":"210","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7986-982X","authenticated-orcid":false,"given":"Masahiko","family":"Miyamoto","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences , Niigata,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiki","family":"Himeda","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Kanazawa Medical University School of Medicine , Ishikawa,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuki","family":"Ishihara","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences , Niigata,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takako","family":"Okuwa","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Kanazawa Medical University School of Medicine , Ishikawa,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8016-5678","authenticated-orcid":false,"given":"Daiki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Omics Unit, Niigata University Graduate School of Medical and Dental Sciences , Niigata,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Nameta","sequence":"additional","affiliation":[{"name":"Electron Microscope Core Facility, Niigata University , Niigata,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Karasawa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences , Niigata,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-4470","authenticated-orcid":false,"given":"Benyapa","family":"Chunhaphinyokul","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences , Niigata,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0525-5953","authenticated-orcid":false,"given":"Yutaka","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Structural Pathology, Kidney Research Center, Niigata University , Niigata,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0229-8061","authenticated-orcid":false,"given":"Nobuyuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Miyagi Cancer Center Research Institute, Medeshima-Shiode , Natori, Miyagi,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7584-5281","authenticated-orcid":false,"given":"Masaya","family":"Higuchi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Kanazawa Medical University School of Medicine , Ishikawa,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6221-1896","authenticated-orcid":false,"given":"Akihiko","family":"Komuro","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences , Niigata,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,2,1]]},"reference":[{"key":"2025021007590752900_r1","first-page":"193","article-title":"Evolution of virulence in picornaviruses","volume":"299","author":"Tracy","year":"2006","journal-title":"Curr. 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