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Here, we provide the first functional characterization of Lem3, the regulatory subunit of the flippase complex in\n                      <jats:italic toggle=\"yes\">Candida albicans<\/jats:italic>\n                      , and reveal its critical role in membrane homeostasis and pathogenesis. We demonstrate that Lem3 localizes to both the endoplasmic reticulum and plasma membrane, consistent with its role in phospholipid translocation. Phenotypic analysis of a\n                      <jats:italic toggle=\"yes\">lem3<\/jats:italic>\n                      \u0394\/\u0394 mutant showed decreased susceptibility to the alkylphosphocholine analog, miltefosine. Concurrently, the mutant was defective in the inward translocation (flip) of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) across the plasma membrane, accompanied by altered levels of ergosterol and sphingolipids, indicating the requirement of Lem3 for maintaining membrane lipid composition. Notably,\n                      <jats:italic toggle=\"yes\">LEM3<\/jats:italic>\n                      deletion suppressed the enhanced phospholipid internalization seen in an\n                      <jats:italic toggle=\"yes\">rta3<\/jats:italic>\n                      \u0394\/\u0394 mutant, suggesting that Rta3 negatively regulates Lem3 activity. The\n                      <jats:italic toggle=\"yes\">lem3<\/jats:italic>\n                      \u0394\/\u0394 strain exhibited increased susceptibility to azole antifungals, likely due to increased membrane permeability and impaired function of the major drug efflux pump Cdr1. Strikingly, the absence of\n                      <jats:italic toggle=\"yes\">LEM3<\/jats:italic>\n                      reversed drug resistance in an azole-resistant clinical isolate, reinforcing its therapeutic relevance. Finally, Lem3 was important for biofilm formation and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      virulence, establishing it as a key determinant of\n                      <jats:italic toggle=\"yes\">C. albicans<\/jats:italic>\n                      pathogenicity. Together, these findings position Lem3 and the flippase machinery as promising targets for antifungal therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Plasma membrane lipid composition, maintained by lipid translocators, is a key determinant of virulence in pathogenic fungi. Here, we demonstrate that Lem3, the regulatory subunit of the flippase complex, by regulating the asymmetric distribution of phospholipids, impacts the expression of virulence traits and modulates drug resistance in\n                      <jats:italic toggle=\"yes\">Candida albicans<\/jats:italic>\n                      . These findings highlight how diverse cellular processes are interconnected through flippase-mediated lipid homeostasis. With the alarming rise in fungal infections and antifungal resistance, targeting lipid translocators such as Lem3 offers a promising avenue for the development of novel therapeutic targets.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02965-25","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:00:19Z","timestamp":1774962019000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Lem3, a phospholipid flippase subunit, influences\n                    <i>Candida albicans<\/i>\n                    pathogenicity through maintenance of plasma membrane asymmetry"],"prefix":"10.1128","volume":"14","author":[{"given":"Pranjali","family":"Agrawal","sequence":"first","affiliation":[{"name":"Yeast Molecular Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru University","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pritam","family":"Kumar","sequence":"additional","affiliation":[{"name":"Yeast Molecular Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru University","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8266-8605","authenticated-orcid":false,"given":"Basharat","family":"Ali","sequence":"additional","affiliation":[{"name":"Yeast Molecular Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru University","place":["New Delhi, India"]},{"id":[{"id":"https:\/\/ror.org\/00k8kkh85","id-type":"ROR","asserted-by":"publisher"}],"name":"Amity Institute of Biotechnology, Amity University Gurugram","place":["Gurugram, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunna","family":"Nabeela","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/025j2nd68","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center","place":["Torrance, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie A. C.","family":"Ikeh","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00d9ah105","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular and Cell Biology, University of California","place":["Merced, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4227-8687","authenticated-orcid":true,"given":"Joachim","family":"Morschh\u00e4user","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00fbnyb24","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Infection Biology, University of W\u00fcrzburg","place":["W\u00fcrzburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7927-9950","authenticated-orcid":true,"given":"David R.","family":"Andes","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y2jtd41","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, 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X Duan HD Hoy MJ Koteva K Spitzer M Guitor AK Puumala E Fiebig AA Hu G Yiu B et al.. 2025. Butyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi. bioRxiv. doi:10.1101\/2025.01.06.630955","DOI":"10.1101\/2025.01.06.630955"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025623"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof10110760"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.011"}],"container-title":["Microbiology Spectrum"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.02965-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.02965-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T13:06:12Z","timestamp":1779282372000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/spectrum.02965-25"}},"subtitle":[],"editor":[{"given":"Robert A.","family":"Arkowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,5]]},"references-count":48,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,5]]}},"alternative-id":["10.1128\/spectrum.02965-25"],"URL":"https:\/\/doi.org\/10.1128\/spectrum.02965-25","relation":{},"ISSN":["2165-0497"],"issn-type":[{"value":"2165-0497","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,5]]},"assertion":[{"value":"2025-10-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02965-25"}}