{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T18:23:10Z","timestamp":1781115790901,"version":"3.54.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T00:00:00Z","timestamp":1641859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970145; 32170203"],"award-info":[{"award-number":["31970145; 32170203"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012669","name":"Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission","doi-asserted-by":"publisher","award":["cstc2021jcyj-msxmX1077"],"award-info":[{"award-number":["cstc2021jcyj-msxmX1077"]}],"id":[{"id":"10.13039\/501100012669","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Cryptococcus neoformans<\/jats:italic> is an opportunistic yeast-like pathogen that mainly infects immunocompromised individuals and causes fatal meningitis. Sexual reproduction can promote the exchange of genetic material between different strains of <jats:italic>C. neoformans<\/jats:italic>, which is one of the reasons leading to the emergence of highly pathogenic and drug-resistant strains of <jats:italic>C. neoformans<\/jats:italic>. Although much research has been done on the regulation mechanism of <jats:italic>Cryptococcus<\/jats:italic> sexual reproduction, there are few studies on the sexual reproduction regulation of <jats:italic>Cryptococcus<\/jats:italic> by the ubiquitin-proteasome system. This study identified an F-box protein, Cdc4, which contains a putative F-box domain and eight WD40 domains. The expression pattern analysis showed that the <jats:italic>CDC4<\/jats:italic> gene was expressed in various developmental stages of <jats:italic>C. neoformans<\/jats:italic>, and the Cdc4 protein was localized in the nucleus of cryptococcal cells. <jats:italic>In vitro<\/jats:italic> stress responses assays showed that the <jats:italic>CDC4<\/jats:italic> overexpression strains are sensitive to SDS and MMS but not Congo red, implying that Cdc4 may regulate the cell membrane integrity and repair of DNA damage of <jats:italic>C. neoformans<\/jats:italic>. Fungal virulence assay showed that although the <jats:italic>cdc4<\/jats:italic>\u0394 mutant grows normally and can produce typical virulence factors such as capsule and melanin, the <jats:italic>cdc4<\/jats:italic>\u0394 mutant completely loses its pathogenicity in a mouse systemic-infection model. Fungal mating assays showed that Cdc4 is also essential for fungal sexual reproduction in <jats:italic>C. neoformans<\/jats:italic>. Although normal mating hyphae were observed during mating, the basidiospores\u2019 production was blocked in bilateral mating between <jats:italic>cdc4<\/jats:italic>\u0394 mutants. Fungal nuclei development assay showed that the nuclei failed to undergo meiosis after fusion inside the basidia during the bilateral mating of <jats:italic>cdc4<\/jats:italic>\u0394 mutants, indicating that Cdc4 is critical to regulating meiosis during cryptococcal mating. In summary, our study revealed that the F-box protein Cdc4 is critical for fungal virulence and sexual reproduction in <jats:italic>C. neoformans<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fcimb.2021.806465","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T05:12:38Z","timestamp":1641877958000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Role of F-box Protein Cdc4 in Fungal Virulence and Sexual Reproduction of Cryptococcus neoformans"],"prefix":"10.3389","volume":"11","author":[{"given":"Ting","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Li","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian-Tao","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Bing","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong-Bao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2772","DOI":"10.1091\/mbc.e05-01-0079","article-title":"Role for the SCFCDC4 Ubiquitin Ligase in Candida Albicans Morphogenesis","volume":"16","author":"Atir-Lande","year":"2005","journal-title":"Mol. 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