{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:27:56Z","timestamp":1785403676733,"version":"3.56.0"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Ganpo Talent Support Program - Project for Cultivating Academic and Technical Leaders in Major Disciplines","award":["20232BCJ23019"],"award-info":[{"award-number":["20232BCJ23019"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32160042"],"award-info":[{"award-number":["32160042"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32200164"],"award-info":[{"award-number":["32200164"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32360050"],"award-info":[{"award-number":["32360050"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81772164"],"award-info":[{"award-number":["81772164"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82360399"],"award-info":[{"award-number":["82360399"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20212BAB216041"],"award-info":[{"award-number":["20212BAB216041"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20224BAB216081"],"award-info":[{"award-number":["20224BAB216081"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Appl Environ Microbiol"],"published-print":{"date-parts":[[2025,12,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Sexual development is a fundamental process that promotes environmental adaptation and the emergence of highly virulent and drug-resistant isolates in the human fungal pathogen\n                      <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                      . Although the genetic factors involved in the sexual life cycle have been extensively investigated in this pathogenic fungus, the critical regulator(s) beyond transcriptional machinery remain poorly understood. Rei1, a conserved C2H2-type zinc finger protein, functions as a 60S ribosome biogenesis factor and plays a crucial role in maintaining cellular growth at low temperature in yeast. In this study, we identified a yeast Rei1-like protein, Rel1, based on the dynamic upregulation of its encoding gene during unisexual reproduction in\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      . Similar to Rei1\u2019s role in yeast, disruption of the\n                      <jats:italic toggle=\"yes\">REL1<\/jats:italic>\n                      gene results in significant growth retardation under low temperature conditions. Consistent with its upregulation during sexual development,\n                      <jats:italic toggle=\"yes\">REL1<\/jats:italic>\n                      deletion compromised the entire sexual cycle, including yeast-hyphae morphogenesis, basidial differentiation, meiosis, and sporulation. RNA-seq analysis revealed that Rei1 plays an important role in the transcriptional activation of key sexual reproduction genes involved in mating response, morphogenesis, and meiosis, suggesting a potential link between ribosome biogenesis and sexual development in\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      . Furthermore,\n                      <jats:italic toggle=\"yes\">REL1<\/jats:italic>\n                      disruption increased susceptibility to the antifungal drug 5\u2019-flucytosine (5\u2032-FC) but enhanced resistance to fluconazole, indicating its differential role in antifungal drug resistance mechanisms. Collectively, this study provides critical insights into how\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      utilizes a conserved ribosome biogenesis factor to coordinate cold resistance, sexual development, and antifungal susceptibility, highlighting the crucial regulatory molecular mechanisms underlying the orchestration of these physiological processes in this ubiquitous pathogenic fungus.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>\n                        <jats:bold>IMPORTANCE<\/jats:bold>\n                      <\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                        , a leading cause of fatal fungal meningitis in immunocompromised individuals, is recognized as a model organism for studying fungal sexual reproduction, as its well-characterized sexual life cycle. Sexual reproduction is a highly energy-intensive process that requires the coordination of various morphological developmental events with dynamic genomic ploidy changes to ensure successful sporulation. However, the conditions that stimulate mating are predominantly driven by nutritional limitation. How\n                        <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                        orchestrated the nutrient-poor conditions to safeguard the sequential developmental events remains elusive. In this study, we characterized a mating-responsible gene,\n                        <jats:italic toggle=\"yes\">REL1<\/jats:italic>\n                        , which encodes a C2H2 zinc-finger protein that is highly homologous to a yeast 60S ribosome biogenesis factor Rei1. Disruption of the\n                        <jats:italic toggle=\"yes\">REL1<\/jats:italic>\n                        gene severely impaired the entire sexual development process. Transcriptomic profiling analysis demonstrated a mating-induced upregulation of multiple Gene Ontology (GO) terms associated with ribosome biogenesis, transmembrane transport, and metabolism. Notably, it also highlighted Rei1\u2019s requirement for activating the key sexual reproduction genes involved in mating response, morphogenesis, and meiosis\/sporulation. These findings demonstrate Rel1\u2019s multifunctionality beyond its previously characterized role in conferring cold tolerance in yeast, implicating a potential link between ribosome biogenesis, sexual development, and antifungal susceptibility in a ubiquitous human fungal pathogen.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aem.01460-25","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T13:47:14Z","timestamp":1764078434000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["A conserved C2H2 zinc finger protein, Rel1, links ribosome biogenesis to sexual development and antifungal susceptibility in a ubiquitous human fungal pathogen"],"prefix":"10.1128","volume":"91","author":[{"given":"Lili","family":"Yan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042v6xz23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Clinical Research Center for Respiratory Diseases","place":["Nanchang, China"]},{"name":"Jiangxi Hospital of China-Japan Friendship Hospital","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042v6xz23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"id":[{"id":"https:\/\/ror.org\/03ekhbz91","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Nephrology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanli","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical College","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0112-764X","authenticated-orcid":true,"given":"Pengjie","family":"Hu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00yd0p282","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01kj4z117","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Pharmaceutical Sciences, Southwest University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Cao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042v6xz23","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042v6xz23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Clinical Research Center for Respiratory Diseases","place":["Nanchang, China"]},{"name":"Jiangxi Hospital of China-Japan Friendship Hospital","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyun","family":"Tian","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00yd0p282","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9568-4171","authenticated-orcid":true,"given":"Xinping","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042v6xz23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Clinical Research Center for Respiratory Diseases","place":["Nanchang, China"]},{"name":"Jiangxi Hospital of China-Japan Friendship Hospital","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0329-0407","authenticated-orcid":true,"given":"Fanglin","family":"Zheng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042v6xz23","id-type":"ROR","asserted-by":"publisher"}],"name":"The Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Clinical Research Center for Respiratory Diseases","place":["Nanchang, China"]},{"name":"Jiangxi Hospital of China-Japan Friendship Hospital","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30243-8"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-024-01062-w"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40249-023-01073-4"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-020518-120210"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0030186"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2011.02.001"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004185"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00147-13"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/mmy\/myv012"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002765"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01433-15"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02785-21"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00198-23"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004849"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001653"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00542-09"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007777"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.01.081"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-030222-113611"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022112699"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1247\/csf.29.1"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.10.3718-3727.2006"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200510080"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.027"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01582-08"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1104\/pp.113.223925"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/1462-2920.14616"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.38683"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00259-13"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110353"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1008245"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108183"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02135-18"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202412514"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.07.064"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003674"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04220"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.117.300656"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2020.103364"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007113"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/msphere.00299-23:e0029923"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3317"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"}],"container-title":["Applied and Environmental Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aem.01460-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aem.01460-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:03:12Z","timestamp":1766498592000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aem.01460-25"}},"subtitle":[],"editor":[{"given":"Irina S.","family":"Druzhinina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":44,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12,23]]}},"alternative-id":["10.1128\/aem.01460-25"],"URL":"https:\/\/doi.org\/10.1128\/aem.01460-25","relation":{},"ISSN":["0099-2240","1098-5336"],"issn-type":[{"value":"0099-2240","type":"print"},{"value":"1098-5336","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]},"assertion":[{"value":"2025-09-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01460-25"}}