{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T12:59:16Z","timestamp":1788094756916,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011413","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000}}],"reference-count":90,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI140719"],"award-info":[{"award-number":["R01AI140719"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020772","name":"Office of Research, University of Georgia","doi-asserted-by":"publisher","award":["Gene E. Michaels endowment"],"award-info":[{"award-number":["Gene E. Michaels endowment"]}],"id":[{"id":"10.13039\/100020772","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Nickel (Ni) is an abundant element on Earth and it can be toxic to all forms of life. Unlike our knowledge of other metals, little is known about the biochemical response to Ni overload. Previous studies in mammals have shown that Ni induces various physiological changes including redox stress, hypoxic responses, as well as cancer progression pathways. However, the primary cellular targets of nickel toxicity are unknown. Here, we used the environmental fungus <jats:italic>Cryptococcus neoformans<\/jats:italic> as a model organism to elucidate the cellular response to exogenous Ni. We discovered that Ni causes alterations in ergosterol (the fungal equivalent of mammalian cholesterol) and lipid biosynthesis, and that the Sterol Regulatory Element-Binding transcription factor Sre1 is required for Ni tolerance. Interestingly, overexpression of the C-4 methyl sterol oxidase gene <jats:italic>ERG25<\/jats:italic>, but not other genes in the ergosterol biosynthesis pathway tested, increases Ni tolerance in both the wild type and the <jats:italic>sre1<\/jats:italic>\u0394 mutant. Overexpression of <jats:italic>ERG25<\/jats:italic> with mutations in the predicted binding pocket to a metal cation cofactor sensitizes <jats:italic>Cryptococcus<\/jats:italic> to nickel and abolishes its ability to rescue the Ni-induced growth defect of <jats:italic>sre1<\/jats:italic>\u0394. As overexpression of a known nickel-binding protein Ure7 or Erg3 with a metal binding pocket similar to Erg25 does not impact on nickel tolerance, Erg25 does not appear to simply act as a nickel sink. Furthermore, nickel induces more profound and specific transcriptome changes in ergosterol biosynthetic genes compared to hypoxia. We conclude that Ni targets the sterol biosynthesis pathway primarily through Erg25 in fungi. Similar to the observation in <jats:italic>C<\/jats:italic>. <jats:italic>neoformans<\/jats:italic>, Ni exposure reduces sterols in human A549 lung epithelial cells, indicating that nickel toxicity on sterol biosynthesis is conserved.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011413","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T17:58:18Z","timestamp":1726509498000},"page":"e1011413","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Nickel tolerance is channeled through C-4 methyl sterol oxidase Erg25 in the sterol biosynthesis pathway"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3407-3027","authenticated-orcid":true,"given":"Amber R.","family":"Matha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Maier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3390-8387","authenticated-orcid":true,"given":"Xiaorong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,16]]},"reference":[{"issue":"33","key":"pgen.1011413.ref001","first-page":"6774","article-title":"Nickel in soils: A review of its distribution and impacts.","volume":"6","author":"YA Iyaka","year":"2011","journal-title":"Scientific Research and Essays"},{"issue":"11","key":"pgen.1011413.ref002","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1039\/c1mt00063b","article-title":"Mechanisms of nickel toxicity in microorganisms.","volume":"3","author":"L Macomber","year":"2011","journal-title":"Metallomics"},{"issue":"1","key":"pgen.1011413.ref003","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S1040-8428(01)00214-1","article-title":"Nickel essentiality, toxicity, and carcinogenicity","volume":"42","author":"E Denkhaus","year":"2002","journal-title":"Critical reviews in oncology\/hematology"},{"issue":"3","key":"pgen.1011413.ref004","doi-asserted-by":"crossref","first-page":"679","DOI":"10.3390\/ijerph17030679","article-title":"Nickel: Human health and environmental toxicology.","volume":"17","author":"G Genchi","year":"2020","journal-title":"International journal of environmental research and public health"},{"issue":"6","key":"pgen.1011413.ref005","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1016\/j.msec.2012.04.025","article-title":"Ni\u2013Cr based dental alloys; 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