{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:18:11Z","timestamp":1790655491948,"version":"4.1.0"},"reference-count":63,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI147541"],"award-info":[{"award-number":["R01AI147541"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI140719"],"award-info":[{"award-number":["R01AI140719"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,11,22]]},"abstract":"<jats:p>\n                    The environmental pathogen\n                    <jats:italic>Cryptococcus neoformans<\/jats:italic>\n                    claims over 180,000 lives each year. Survival of this basidiomycete at host CO\n                    <jats:sub>2<\/jats:sub>\n                    concentrations has only recently been considered an important virulence trait. Through screening gene knockout libraries constructed in a CO\n                    <jats:sub>2<\/jats:sub>\n                    -tolerant clinical strain, we found mutations leading to CO\n                    <jats:sub>2<\/jats:sub>\n                    sensitivity are enriched in pathways activated by heat stress, including calcineurin, Ras1-Cdc24, cell wall integrity, and\n                    <jats:italic>R<\/jats:italic>\n                    egulator of\n                    <jats:italic>A<\/jats:italic>\n                    ce2 and\n                    <jats:italic>M<\/jats:italic>\n                    orphogenesis (RAM). Overexpression of Cbk1, the conserved terminal kinase of the RAM pathway, partially restored defects of these mutants at host CO\n                    <jats:sub>2<\/jats:sub>\n                    or temperature levels. In ascomycetes such as\n                    <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    and\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    , transcription factor Ace2 is an important target of Cbk1, activating genes responsible for cell separation. However, no Ace2 homolog or any downstream component of the RAM pathway has been identified in basidiomycetes. Through in vitro evolution and comparative genomics, we characterized mutations in suppressors of\n                    <jats:italic>cbk1<\/jats:italic>\n                    \u0394 in\n                    <jats:italic>C. neoformans<\/jats:italic>\n                    that partially rescued defects in CO\n                    <jats:sub>2<\/jats:sub>\n                    tolerance, thermotolerance, and morphology. One suppressor is the RNA translation repressor Ssd1, which is highly conserved in ascomycetes and basidiomycetes. The other is a novel ribonuclease domain-containing protein, here named\n                    <jats:italic>PSC1<\/jats:italic>\n                    , which is present in basidiomycetes and humans but surprisingly absent in most ascomycetes. Loss of Ssd1 in\n                    <jats:italic>cbk1<\/jats:italic>\n                    \u0394 partially restored cryptococcal ability to survive and amplify in the inhalation and intravenous murine models of cryptococcosis. Our discoveries highlight the overlapping regulation of CO\n                    <jats:sub>2<\/jats:sub>\n                    tolerance and thermotolerance, the essential role of the RAM pathway in cryptococcal adaptation to the host condition, and the potential importance of post-transcriptional control of virulence traits in this global pathogen.\n                  <\/jats:p>","DOI":"10.7554\/elife.82563","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T08:00:23Z","timestamp":1669190423000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.82563","source":"Crossref","is-referenced-by-count":37,"title":["The RAM signaling pathway links morphology, thermotolerance, and CO2 tolerance in the global fungal pathogen Cryptococcus neoformans"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8244-6190","authenticated-orcid":true,"given":"Benjamin J","family":"Chadwick","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00te3t702","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant Biology, University of Georgia","place":["Athens, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuyetnhu","family":"Pham","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00te3t702","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant Biology, University of Georgia","place":["Athens, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Xie","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00te3t702","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, University of Georgia","place":["Athens, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura C","family":"Ristow","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036jqmy94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa","place":["Iowa City, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian J","family":"Krysan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036jqmy94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa","place":["Iowa City, United States"]},{"id":[{"id":"https:\/\/ror.org\/036jqmy94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa","place":["Iowa City, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3390-8387","authenticated-orcid":true,"given":"Xiaorong","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00te3t702","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant Biology, University of Georgia","place":["Athens, United States"]},{"id":[{"id":"https:\/\/ror.org\/00te3t702","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, University of Georgia","place":["Athens, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1016\/j.cub.2005.09.047","article-title":"Carbonic anhydrase and CO2 sensing during Cryptococcus neoformans growth, differentiation, and virulence","volume":"15","author":"Bahn","year":"2005","journal-title":"Current Biology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"3122","DOI":"10.1091\/mbc.e06-02-0113","article-title":"A unique fungal two-component system regulates stress responses, drug sensitivity, sexual development, and virulence of cryptococcus neoformans","volume":"17","author":"Bahn","year":"2006","journal-title":"Molecular Biology of the Cell"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/j.mib.2006.09.003","article-title":"Co2 sensing in fungi and beyond","volume":"9","author":"Bahn","year":"2006","journal-title":"Current Opinion in Microbiology"},{"key":"bib4","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12907-x","article-title":"Thermotolerance in the pathogen cryptococcus neoformans is linked to antigen masking via mrna decay-dependent reprogramming","volume":"10","author":"Bloom","year":"2019","journal-title":"Nature Communications"},{"key":"bib5","article-title":"Picard tools. broad institute","volume-title":"GitHub Repository","author":"Broad_Institute","year":"2022","unstructured":"Broad_Institute. 2022. 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