{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:02:17Z","timestamp":1781103737720,"version":"3.54.1"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"17","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["Intramural Research"],"award-info":[{"award-number":["Intramural Research"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4,29]]},"abstract":"<jats:p>\n                    UDP-glucuronic acid (UDP-GlcUA) is a nucleotide sugar essential for various biological processes in many organisms, and its excess within the cell can disrupt cellular functions. In\n                    <jats:italic>Cryptococcus<\/jats:italic>\n                    , mutations in the\n                    <jats:italic>UXS1<\/jats:italic>\n                    gene which encodes an enzyme responsible for converting UDP-GlcUA into UDP-xylose, result in excessive accumulation of UDP-GlcUA and confer resistance to the antifungal drug 5-fluorocytosine. Here, we demonstrate that elevation of UDP-GlcUA affects several cellular processes in\n                    <jats:italic>Cryptococcus gattii<\/jats:italic>\n                    , including growth rate, ability to grow under various stress conditions and resistance to fluorinated pyrimidine analogs. RNA-seq analyses of the\n                    <jats:italic>uxs1\u0394<\/jats:italic>\n                    mutant identify three acid protease genes, notably\n                    <jats:italic>PEP401<\/jats:italic>\n                    , that are differentially expressed. The absence of\n                    <jats:italic>PEP401<\/jats:italic>\n                    in the\n                    <jats:italic>uxs1\u0394<\/jats:italic>\n                    background significantly reduces UDP-GlcUA levels and reverts all the phenotypes of the\n                    <jats:italic>uxs1\u0394<\/jats:italic>\n                    mutant to the wild-type characteristics. High levels of UDP-GlcUA not only regulate expression of\n                    <jats:italic>PEP401<\/jats:italic>\n                    at RNA and protein levels but also enhance the proteolytic activity of total protein extracts in a\n                    <jats:italic>PEP401<\/jats:italic>\n                    -dependent manner, establishing a functional link between nucleotide sugar metabolism and proteolytic regulation. Moreover, the UDP-GlcUA transporter gene,\n                    <jats:italic>UUT1<\/jats:italic>\n                    , can further modulate the levels of UDP-GlcUA in the\n                    <jats:italic>uxs1\u0394 pep401\u0394<\/jats:italic>\n                    double mutant and manifests drug resistance phenotypes observed in the\n                    <jats:italic>uxs1\u0394<\/jats:italic>\n                    mutant. Collectively, these findings reveal a previously unrecognized regulatory network that links UDP-GlcUA metabolism to protease-mediated cellular processes and the transport of UDP-GlcUA. This interaction provides a foundation for targeting nucleotide sugar metabolism and protease regulation in the development of enhanced therapeutic strategies against cryptococcosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2503960122","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T13:37:33Z","timestamp":1745415453000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Elevated UDP-glucuronic acid levels mend drug resistance and stress responses via a protease and a transporter in\n                    <i>Cryptococcus gattii<\/i>"],"prefix":"10.1073","volume":"122","author":[{"given":"Sujiraphong","family":"Pharkjaksu","sequence":"first","affiliation":[{"name":"Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Cai","sequence":"additional","affiliation":[{"name":"Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Walter","sequence":"additional","affiliation":[{"name":"Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun C.","family":"Chang","sequence":"additional","affiliation":[{"name":"Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3383-1428","authenticated-orcid":false,"given":"Kyung J.","family":"Kwon-Chung","sequence":"additional","affiliation":[{"name":"Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004404"},{"key":"e_1_3_4_2_2","volume-title":"WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action","author":"WHO","year":"2022","unstructured":"WHO, WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action (World Health Organization, Geneva, 2022)."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/femsyr\/fov106"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02708-21"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/649858"},{"key":"e_1_3_4_6_2","first-page":"424","article-title":"Clinical use of systemic antifungal agents","volume":"7","author":"Benson J. 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Deposited 14 February 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2503960122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T13:38:15Z","timestamp":1745415495000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2503960122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,23]]},"references-count":46,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2025,4,29]]}},"alternative-id":["10.1073\/pnas.2503960122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2503960122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,23]]},"assertion":[{"value":"2025-02-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2503960122"}}