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The purpose of this study was to investigate the role of autophagy inhibition by 3\u2010methyladenine (3\u2010MA) on murine cytomegalovirus (MCMV) replication and whether it is associated with caspase\u20103 dependent apoptosis.\u00a0The eyecup isolated from adult C57BL\/6J mice (6\u20138 weeks old) and mouse embryo fibroblast cells (MEFs) were infected with MCMV K181 strain, followed by the treatment of 3\u2010methyladenine (3\u2010MA), chloroquine, or rapamycin to block or stimulate autophagy.\u00a0In cultured MEFs, the ratio of LC3I\/II was reduced at 24 hours\u00a0post infection (hpi), but was increased at 48\u2009hpi\u00a0In the eyecup culture, LC3I\/II ratio was also decreased at 4 and 7 days post infection (dpi). In addition, caspase\u20103 cleavage was increased at 48\u2009hpi\u00a0in MEFs and also elevated in MCMV infected eyecups at 4, 7, 10, and 14\u2009dpi. 3\u2010MA treatment significantly inhibited the virus replication in MEFs and eyecups. The expression of early antigen (EA) of MCMV was also decreased in MEFs and eyecups. Meanwhile, cleaved caspase\u20103 dependent cell death was promoted with the presence of 3\u2010MA in MCMV infected MEFs and eyecups, while RIPK1\/RIPK3\/MLKL pathway was inhibited by 3\u2010MA in eyecups.\u00a0Inhibition of autophagy by 3\u2010MA restricts virus replication and promotes caspase\u20103 dependent apoptosis in the eyecup and MEFs with MCMV infection. It can be explained that during the early period of MCMV infection, the suppressed autophagy process directly reduced virus release, but later caspase\u20103 dependent apoptosis dominated and resulted in decreased virus replication.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jmv.26787","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T00:29:22Z","timestamp":1610670562000},"page":"5001-5016","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Inhibition of autophagy by 3\u2010methyladenine restricts murine cytomegalovirus replication"],"prefix":"10.1002","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-2714","authenticated-orcid":false,"given":"Xinyan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pediatrics Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology  Wuhan Hubei 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