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The mechanisms of filamentation in the emerging multidrug-resistant fungal pathogen <jats:italic>Candida auris<\/jats:italic> are poorly understood. Here, we show that exposure of <jats:italic>C<\/jats:italic>. <jats:italic>auris<\/jats:italic> to glycerol triggers a rod-like filamentation-competent (RL-FC) phenotype, which forms elongated filamentous cells after a prolonged culture period. Whole-genome sequencing analysis reveals that all RL-FC isolates harbor a mutation in the C<jats:sub>2<\/jats:sub>H<jats:sub>2<\/jats:sub> zinc finger transcription factor-encoding gene <jats:italic>GFC1<\/jats:italic> (Gfc1 variants). Deletion of <jats:italic>GFC1<\/jats:italic> leads to an RL-FC phenotype similar to that observed in Gfc1 variants. We further demonstrate that <jats:italic>GFC1<\/jats:italic> mutation causes enhanced fatty acid \u03b2-oxidation metabolism and thereby promotes RL-FC\/filamentous growth. This regulation is achieved through a Multiple Carbon source Utilizer (Mcu1)-dependent mechanism. Interestingly, both the evolved RL-FC isolates and the <jats:italic>gfc1<\/jats:italic>\u0394 mutant exhibit an enhanced ability to colonize the skin. Our results reveal that glycerol-mediated <jats:italic>GFC1<\/jats:italic> mutations are beneficial during <jats:italic>C<\/jats:italic>. <jats:italic>auris<\/jats:italic> skin colonization and infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012362","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T19:11:49Z","timestamp":1720465909000},"page":"e1012362","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["A single gene mutation underpins metabolic adaptation and acquisition of filamentous competence in the emerging fungal pathogen Candida auris"],"prefix":"10.1371","volume":"20","author":[{"given":"Yuchen","family":"Deng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaihu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Bing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiushi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanghua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqing","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6109-3480","authenticated-orcid":true,"given":"Li","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,8]]},"reference":[{"issue":"1","key":"ppat.1012362.ref001","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1348-0421.2008.00083.x","article-title":"Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital","volume":"53","author":"K Satoh","year":"2009","journal-title":"Microbiol Immunol"},{"issue":"10","key":"ppat.1012362.ref002","doi-asserted-by":"crossref","first-page":"e1008921","DOI":"10.1371\/journal.ppat.1008921","article-title":"Candida auris: Epidemiology, biology, antifungal resistance, and virulence","volume":"16","author":"H Du","year":"2020","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1012362.ref003","doi-asserted-by":"crossref","first-page":"489","DOI":"10.7326\/M22-3469","article-title":"Worsening spread of Candida auris in the United States, 2019 to 2021","volume":"176","author":"M Lyman","year":"2023","journal-title":"Ann Intern Med"},{"issue":"6","key":"ppat.1012362.ref004","doi-asserted-by":"crossref","first-page":"e396","DOI":"10.1016\/S2666-5247(23)00143-X","article-title":"Emergence of resistant Candida auris","volume":"4","author":"R. 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