{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T14:53:07Z","timestamp":1781621587705,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,13]]},"group-title":"Microbiology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Cryptococcus neoformans<\/jats:italic>\n                  is the leading cause of fungal meningitis in immunocompromised patients. Alveolar macrophages are the first line of defense against\n                  <jats:italic>Cryptococcus<\/jats:italic>\n                  infection. Our previous study showed that deletion of Cdc50, the regulatory subunit of P4-ATPase (lipid flippase) complex, results in increased phagocytosis and macrophage killing, and avirulence in animal models. However, how fungal flippase dysfunction modulates\n                  <jats:italic>Cryptococcus<\/jats:italic>\n                  -macrophage interaction remains unknown. Here we identify Cdc50 as a central determinant of membrane lipid homeostasis, extracellular vesicle (EV) biogenesis and macrophage responses in\n                  <jats:italic>C. neoformans<\/jats:italic>\n                  . Our whole cell lipidomic analysis revealed that loss of Cdc50 disrupted membrane lipid homeostasis leading to phospholipid enrichment in\n                  <jats:italic>cdc50\u0394<\/jats:italic>\n                  mutant, and a reduction in fatty acid production accompanied by pronounced ultrastructural defects in membrane architecture. Loss of Cdc50 also induced a hyper-vesiculating phenotype, with\n                  <jats:italic>cdc50\u0394<\/jats:italic>\n                  producing significantly more extracellular vesicles (EVs) than wild type H99 cells. Lipidomic profiling of\n                  <jats:italic>cdc50\u0394<\/jats:italic>\n                  EVs revealed enrichment of phospholipids, including phosphatidylserine (PS), indicating active lipid sorting during vesicle biogenesis. Functional analysis showed that EVs from the wildtype H99 suppress phagocytosis whereas\n                  <jats:italic>cdc50\u0394<\/jats:italic>\n                  EVs enhance phagocytosis, indicating a differential macrophage priming. Despite increased PS externalization in\n                  <jats:italic>cdc50\u0394<\/jats:italic>\n                  cells and EVs, macrophage recognition and uptake occur independent of PS-mediated efferocytosis pathways, including PS receptor MertK. Following macrophage uptake,\n                  <jats:italic>cdc50\u0394<\/jats:italic>\n                  were intrinsically vulnerable to macrophage killing due to rapid phagosome acidification. Together, we demonstrate that Cdc50 dependent lipid homeostasis regulates EV production, lipid composition, membrane architecture and drives the intracellular fate of\n                  <jats:italic>C. neoformans<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Cryptococcus neoformans<\/jats:italic>\n                    is the leading cause of fungal meningitis in immunocompromised individuals. Understanding how this pathogen evades host immune mediated clearance is essential for developing new treatment strategies. Here, we demonstrated that Cdc50, the regulatory subunit of fungal lipid flippase complex, regulates membrane lipid homeostasis that governs extracellular vesicles (EV) biogenesis and macrophage immune responses. Loss of Cdc50 drives global membrane lipid remodeling, hyper-production of phospholipid enriched EVs that enhance macrophage phagocytosis, while the wild-type EV reduce macrophage phagocytosis. Contrary to the prevailing assumption that phosphatidylserine (PS) externalization on the fungal surfaces mimics the mammalian \u201ceat-me signal\u201d, we show fungal PS does not engage canonical PS receptor MertK, revealing a fundamental difference between fungal and mammalian PS biology. Furthermore,\n                    <jats:italic>cdc50<\/jats:italic>\n                    \u0394 cells are unable to resist phagosomal acidification, rendering them susceptible to macrophage killing. These findings establish how phospholipid homeostasis contributes to early host-pathogen interactions and serves as a compelling antifungal target in cryptococcosis.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.12.731820","type":"posted-content","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T21:00:17Z","timestamp":1781384417000},"source":"Crossref","is-referenced-by-count":0,"title":["Lipid Flippase Mediated Membrane Asymmetry Governs Extracellular Vesicles Biogenesis and Host Interactions in\n                  <i>Cryptococcus neoformans<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9276-095X","authenticated-orcid":false,"given":"Siddhi","family":"Pawar","sequence":"first","affiliation":[{"name":"Public Health Research Institute, Rutgers School of Graduate Studies, Newark, New Jersey, USA,"},{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutger University Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Public Health Research Institute, Rutgers School of Graduate Studies, Newark, New Jersey, USA,"},{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutger University Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Varsanyi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutger University Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varsha","family":"Gadiyar","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutger University Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3918-7971","authenticated-orcid":false,"given":"Samantha","family":"Avina","sequence":"additional","affiliation":[{"name":"Public Health Research Institute, Rutgers School of Graduate Studies, Newark, New Jersey, USA,"},{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutger University Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Birge","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutger University Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Xue","sequence":"additional","affiliation":[{"name":"Public Health Research Institute, Rutgers School of Graduate Studies, Newark, New Jersey, USA,"},{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutger University Newark, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061607051156000_2026.06.12.731820v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30243-8"},{"key":"2026061607051156000_2026.06.12.731820v1.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012513-104653"},{"key":"2026061607051156000_2026.06.12.731820v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.60.080805.142102"},{"key":"2026061607051156000_2026.06.12.731820v1.4","doi-asserted-by":"crossref","unstructured":"Wang Y , Pawar S , Dutta O , Wang K , Rivera A , Xue C . 2022. 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