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Here, we investigated the role of the UPR pathway in <jats:italic>C. deuterogattii<\/jats:italic>, which causes pneumonia and systemic cryptococcosis, even in immunocompetent individuals. In response to ER stress, <jats:italic>C. deuterogattii<\/jats:italic> Ire1 triggers unconventional splicing of <jats:italic>HXL1<\/jats:italic> to induce the expression of UPR target genes such as <jats:italic>KAR2<\/jats:italic>, <jats:italic>DER1<\/jats:italic>, <jats:italic>ALG7<\/jats:italic>, and <jats:italic>ERG29<\/jats:italic>. Furthermore, <jats:italic>C. deuterogattii<\/jats:italic> Ire1 is required for growth at mammalian body temperature, similar to <jats:italic>C. neoformans<\/jats:italic> Ire1. However, deletion of <jats:italic>HXL1<\/jats:italic> does not significantly affect the growth of <jats:italic>C. deuterogattii<\/jats:italic> at 37\u2009\u00b0C, which is in contrast to the indispensable role of <jats:italic>HXL1<\/jats:italic> in the growth of <jats:italic>C. neoformans<\/jats:italic> at 37\u2009\u00b0C. Nevertheless, both <jats:italic>C. deuterogattii ire1<\/jats:italic>\u0394 and <jats:italic>hxl1<\/jats:italic>\u0394 mutants are avirulent in a murine model of systemic cryptococcosis, suggesting that a non-thermotolerance phenotypic trait also contributes to the role of the UPR pathway in the virulence of pathogenic <jats:italic>Cryptococcus<\/jats:italic> species. In conclusion, the UPR pathway plays redundant and distinct roles in the virulence of members of the pathogenic <jats:italic>Cryptococcus<\/jats:italic> species complex.<\/jats:p>","DOI":"10.1038\/s41598-018-26405-5","type":"journal-article","created":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T12:03:13Z","timestamp":1526904193000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Evolutionarily Conserved and Divergent Roles of Unfolded Protein Response (UPR) in the Pathogenic Cryptococcus Species Complex"],"prefix":"10.1038","volume":"8","author":[{"given":"Kwang-Woo","family":"Jung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Tae","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna F.","family":"Averette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Hoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Everitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Heitman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9573-5752","authenticated-orcid":false,"given":"Yong-Sun","family":"Bahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,5,25]]},"reference":[{"key":"26405_CR1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1093\/oxfordjournals.aje.a113861","volume":"120","author":"KJ Kwon-Chung","year":"1984","unstructured":"Kwon-Chung, K. 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