{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:20:17Z","timestamp":1791390017823,"version":"4.3.3"},"reference-count":72,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"MOH | National Medical Research Council","award":["OFIRG\/0055\/2019"],"award-info":[{"award-number":["OFIRG\/0055\/2019"]}]},{"name":"MOH | National Medical Research Council","award":["OFIRG21jun-0058"],"award-info":[{"award-number":["OFIRG21jun-0058"]}]},{"DOI":"10.13039\/501100001348","name":"Agency for Science, Technology and Research","doi-asserted-by":"crossref","award":["HTPO SEED_ID_ C211418006"],"award-info":[{"award-number":["HTPO SEED_ID_ C211418006"]}],"id":[{"id":"10.13039\/501100001348","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2023,12,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The emergence and nosocomial spread of the multidrug-resistant\n            <jats:italic>Candida auris<\/jats:italic>\n            pose a severe public health threat. Most\n            <jats:italic>C. auris<\/jats:italic>\n            clinical isolates are fluconazole resistant. In this study, we conduct transposon-mediated screens to profile genes whose inactivation causes fluconazole resistance in\n            <jats:italic>C. auris<\/jats:italic>\n            . We discover that mutation of genes encoding the Ubr2\/Mub1 ubiquitin-ligase complex results in high fluconazole resistance by stabilizing the transcription activator, Rpn4. Global transcriptomic analysis, quantitative PCR, and combinatorial gene deletion reveal that Rpn4 causes fluconazole resistance by upregulating four efflux pump genes,\n            <jats:italic>SNQ21<\/jats:italic>\n            ,\n            <jats:italic>SNQ22<\/jats:italic>\n            ,\n            <jats:italic>MDR1<\/jats:italic>\n            , and\n            <jats:italic>CDR1<\/jats:italic>\n            , increasing efflux activity of the cell. Rpn4 autoactivates its own expression by binding to a PACE element in its promoter, forming a positive autoregulatory loop. Rpn4 also promotes\n            <jats:italic>CDR1<\/jats:italic>\n            expression by binding to a PACE element in the\n            <jats:italic>CDR1<\/jats:italic>\n            promoter. Furthermore, using the published genome sequence data of 304 clinical isolates, we identified a\n            <jats:italic>UBR2<\/jats:italic>\n            A316T mutation in isolates from clades I and III. Although complementation of the\n            <jats:italic>ubr2<\/jats:italic>\n            \u0394 mutant with the\n            <jats:italic>UBR2<\/jats:italic>\n            <jats:sup>A316T<\/jats:sup>\n            allele resulted in increased susceptibility to fluconazole, the\n            <jats:italic>UBR2<\/jats:italic>\n            <jats:sup>A316T<\/jats:sup>\n            mutant was still more resistant to fluconazole compared to wild type, suggesting that acquisition of the mutation is sufficient to confer an increase in fluconazole resistance. In conclusion, this study identifies Rpn4 as a critical transcription factor that regulates fluconazole resistance via the Rpn4-efflux pump axis in\n            <jats:italic>C. auris<\/jats:italic>\n            .\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              <jats:italic>Candida auris<\/jats:italic>\n              is a recently emerged pathogenic fungus of grave concern globally due to its resistance to conventional antifungals. This study takes a whole-genome approach to explore how\n              <jats:italic>C. auris<\/jats:italic>\n              overcomes growth inhibition imposed by the common antifungal drug fluconazole. We focused on gene disruptions caused by a \u201cjumping genetic element\u201d called transposon, leading to fluconazole resistance. We identified mutations in two genes, each encoding a component of the Ubr2\/Mub1 ubiquitin-ligase complex, which marks the transcription regulator Rpn4 for degradation. When either protein is absent, stable Rpn4 accumulates in the cell. We found that Rpn4 activates the expression of itself as well as the main drug efflux pump gene\n              <jats:italic>CDR1<\/jats:italic>\n              by binding to a PACE element in the promoter. Furthermore, we identified an amino acid change in Ubr2 in many resistant clinical isolates, contributing to Rpn4 stabilization and increased fluconazole resistance.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.02688-23","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T14:01:43Z","timestamp":1701180103000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["The transcription factor Rpn4 activates its own transcription and induces efflux pump expression to confer fluconazole resistance in\n            <i>Candida auris<\/i>"],"prefix":"10.1128","volume":"14","author":[{"given":"Eve W. L.","family":"Chow","sequence":"first","affiliation":[{"name":"Infectious Diseases Labs, Agency for Science, Technology and Research, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yabing","family":"Song","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tsinghua University, Beijing, China"},{"name":"State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxin","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tsinghua University, Beijing, China"},{"name":"State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Xu","sequence":"additional","affiliation":[{"name":"Infectious Diseases Labs, Agency for Science, Technology and Research, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbin","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tsinghua University, Beijing, China"},{"name":"Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Chen","sequence":"additional","affiliation":[{"name":"Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China"},{"name":"Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6161-4629","authenticated-orcid":false,"given":"Jiaxin","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1211-2822","authenticated-orcid":true,"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Infectious Diseases Labs, Agency for Science, Technology and Research, Singapore, Singapore"},{"name":"Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw696"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1714373"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13756-016-0132-5"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.03364-19"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2019.05.008"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1348-0421.2008.00083.x"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw691"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006290"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41426-018-0095-0"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00921-17"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhin.2017.11.015"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/myc.12781"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid2302.161486"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00189-16"},{"key":"e_1_3_5_16_2","unstructured":"(CDC) CfDCaP. 2019. National notifiable diseases surveillance system (NNDSS) 2019 national notifiable conditions on center for disease control and prevention (CDC)"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30316-X"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid2410.180649"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab327"},{"key":"e_1_3_5_20_2","first-page":"277","article-title":"The antibiotic resistance crisis: part 1: causes and threats","volume":"40","author":"Ventola CL","year":"2015","unstructured":"Ventola CL. 2015. The antibiotic resistance crisis: part 1: causes and threats. Pharm Ther 40:277\u2013283.","journal-title":"Pharm Ther"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkx480"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01624-18"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02663-20"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07779-6"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/Spectrum.01585-21"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00334-18"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00346-19"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00057-19"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.01445"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20183-3"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.3.6.1639-1652.2004"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.105.054767"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0030164"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2008.06309.x"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00365-20"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00279-20"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-021-00915-x"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01787-07"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2021.1928410"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410085200"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-5793(99)00467-6"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.071022298"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00554-20"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011338"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.06.105"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2007.05.015"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00051-08"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/44.1.27"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2009.07.001"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01252-16"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2002.02823.x"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.4.1384-1392.2006"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","unstructured":"Evans R O\u2019Neill M Pritzel A Antropova N Senior A Green T \u017d\u00eddek A Bates R Blackwell S Yim J Ronneberger O Bodenstein S Zielinski M Bridgland A Potapenko A Cowie A Tunyasuvunakool K Jain R Clancy E Kohli P Jumper J Hassabis D. 2021. Protein complex prediction with Alphafold-multimer. Biorxiv. doi:10.1101\/2021.10.04.463034","DOI":"10.1101\/2021.10.04.463034"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.03333-20"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27545-5"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2010.107"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt919"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000783"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00535-10"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.02173"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.12.056"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/0168-9525(89)90049-8"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05931.x"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00277-10"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1534\/g3.120.401595"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06944-1"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600195"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0201-4"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_5_71_2","doi-asserted-by":"publisher","DOI":"10.1007\/7651_2020_307"},{"key":"e_1_3_5_72_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_3_5_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"e_1_3_5_74_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.02688-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.02688-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T20:05:59Z","timestamp":1703275559000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.02688-23"}},"subtitle":[],"editor":[{"given":"Judith","family":"Berman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,12,19]]},"references-count":72,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,12,19]]}},"alternative-id":["10.1128\/mbio.02688-23"],"URL":"https:\/\/doi.org\/10.1128\/mbio.02688-23","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,19]]},"assertion":[{"value":"2023-10-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02688-23"}}