{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:30:55Z","timestamp":1789731055428,"version":"4.0.1"},"reference-count":69,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF20OC0060298"],"award-info":[{"award-number":["NNF20OC0060298"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF21OC0071296"],"award-info":[{"award-number":["NNF21OC0071296"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GU 1133\/13-1"],"award-info":[{"award-number":["GU 1133\/13-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["INST 213\/886-1"],"award-info":[{"award-number":["INST 213\/886-1"]}],"id":[{"id":"10.13039\/501100001659","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":[[2026,5,12]]},"abstract":"<jats:p>Saponins are a class of plant-derived amphiphile defense compounds that disrupt cellular membranes, yet the basis for their selective toxicity remains unclear. Because membrane sterols diverged across the three major eukaryotic kingdoms from a shared biosynthetic precursor, we tested whether sterol identity governs membrane susceptibility to saponins. Using yeast, sterol supplementation, synthetic liposomes, and molecular dynamics simulations, we compared membranes containing zoosterols, mycosterols, or phytosterols. When a panel of structurally different saponins was tested, reduced ergosterol levels in yeast were consistently associated with decreased lytic activity. A similar reduction in susceptibility was observed when ergosterol was replaced by phytosterols in yeast. These trends were recapitulated in a simplified membrane system, where the sterol identity in large unilamellar vesicles strongly influenced saponin-induced lysis. The triterpenoid saponin \u03b1-hederin efficiently lysed membranes enriched in cholesterol or ergosterol, whereas membranes containing plant phytosterols were markedly resistant. In contrast, the steroidal saponin digitonin exhibited lower lytic activity and limited sterol selectivity. Molecular dynamic simulations revealed sterol-dependent clustering and membrane responses that paralleled experimental susceptibility. Together, these findings support a two-parameter model where structural characteristics of saponins together with sterol identity in the membrane are a primary determinant of saponin-induced membrane disruption. The differential compatibility between saponins and sterol classes provides a mechanistic framework for understanding cross-kingdom selectivity and sheds light on how plants avoid self-toxicity while deploying saponins for defense.<\/jats:p>","DOI":"10.1073\/pnas.2523859123","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T09:47:13Z","timestamp":1778579233000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Sterol divergence across eukaryotic kingdoms determines membrane susceptibility to saponins, a class of plant defense compounds"],"prefix":"10.1073","volume":"123","author":[{"given":"Malbor","family":"Dervishi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant and Environmental Sciences, University of Copenhagen","place":["Frederiksberg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8042-5241","authenticated-orcid":false,"given":"Jan","family":"G\u00fcnther","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant and Environmental Sciences, University of Copenhagen","place":["Frederiksberg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4744-4621","authenticated-orcid":false,"given":"Jinhui","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y64my43","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemical and Biological Engineering, University of Buffalo","place":["Amherst"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huriye Deniz","family":"Uzun","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant and Environmental Sciences, University of Copenhagen","place":["Frederiksberg, Denmark"]},{"id":[{"id":"https:\/\/ror.org\/04tsk2644","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8617-2393","authenticated-orcid":false,"given":"Hans Christian Bruun","family":"Hansen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant and Environmental Sciences, University of Copenhagen","place":["Frederiksberg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4889-0829","authenticated-orcid":false,"given":"Thomas","family":"G\u00fcnther Pomorski","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant and Environmental Sciences, University of Copenhagen","place":["Frederiksberg, Denmark"]},{"id":[{"id":"https:\/\/ror.org\/04tsk2644","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1153-8394","authenticated-orcid":false,"given":"Anja Thoe","family":"Fuglsang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant and Environmental Sciences, University of Copenhagen","place":["Frederiksberg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9202-782X","authenticated-orcid":false,"given":"Viviana","family":"Monje","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y64my43","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemical and Biological Engineering, University of Buffalo","place":["Amherst"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4100-115X","authenticated-orcid":false,"given":"S\u00f8ren","family":"Bak","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035b05819","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Plant and Environmental Sciences, University of Copenhagen","place":["Frederiksberg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.41.110306.130315"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06170-w"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nplants.2016.205"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13211-4"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2006.10.008"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-arplant-050312-120229"},{"key":"e_1_3_5_7_2","doi-asserted-by":"crossref","unstructured":"P. Xu B. Yu \u201cChemical synthesis of saponins: An update\u201d in Advances in Carbohydrate Chemistry and Biochemistry D. C. Baker Ed. (Elsevier 2021) pp. 1\u201362 10.1016\/bs.accb.2021.11.001.","DOI":"10.1016\/bs.accb.2021.11.001"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2003.11.014"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2011.01.015"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1079\/BJN2002725"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/sci3040044"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lwt.2017.08.077"},{"key":"e_1_3_5_13_2","first-page":"1","article-title":"Natural and synthetic saponins as vaccine adjuvants","volume":"9","author":"Wang P.","year":"2021","unstructured":"P. Wang, Natural and synthetic saponins as vaccine adjuvants. Vaccines (Basel) 9, 1\u201318 (2021).","journal-title":"Vaccines (Basel)"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11101-020-09722-4"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.3109\/10409238.2014.953628"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.407635"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10886-025-01666-3"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2010.11.014"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1039\/C4OB01652A"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.08.011"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsabm.2c00928"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphc.202000219"},{"key":"e_1_3_5_23_2","doi-asserted-by":"crossref","unstructured":"C. Wang Glycosylation pattern controls solubility micellization and aggregation of structurally defined ivy-derived triterpenoid saponins. JCIS Open 22 100177 (2026).","DOI":"10.1016\/j.jciso.2026.100177"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1150021"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-40308-0"},{"key":"e_1_3_5_26_2","first-page":"1","article-title":"Functional analysis of the C-5 sterol desaturase PcErg3 in the sterol auxotrophic oomycete pathogen Phytophthora capsici","volume":"13","author":"Wang W.","year":"2022","unstructured":"W. Wang , Functional analysis of the C-5 sterol desaturase PcErg3 in the sterol auxotrophic oomycete pathogen Phytophthora capsici. Front. Microbiol. 13, 1\u201311 (2022).","journal-title":"Front. Microbiol."},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/la4049902"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp5074939"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.5.1710-1714.2006"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2012.12.010"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00894-009-0523-0"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-022-01054-y"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b04387"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2008.03.001"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11101-009-9121-0"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/nph.18763"},{"key":"e_1_3_5_37_2","first-page":"177","volume-title":"Growth and Maintenance of Yeast BT\u2013Two-Hybrid Systems\u2014Methods and Protocols","author":"Bergman L. W.","year":"2001","unstructured":"L. W. Bergman, Growth and Maintenance of Yeast BT\u2013Two-Hybrid Systems\u2014Methods and Protocols, P. N. MacDonald, Ed. (Humana Press, 2001), p. 177, 336, 9\u201314."},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02535438"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.20212"},{"key":"e_1_3_5_40_2","first-page":"27","article-title":"Isolation of yeast plasma membranes","volume":"313","author":"Panaretou B.","year":"2006","unstructured":"B. Panaretou, P. Piper, Isolation of yeast plasma membranes. Methods Mol. Biol. 313, 27\u201332 (2006).","journal-title":"Methods Mol. Biol."},{"key":"e_1_3_5_41_2","first-page":"1","article-title":"In vitro assay to evaluate cation transport of ionophores","volume":"22","author":"Uzun H. D.","year":"2022","unstructured":"H. D. Uzun, M. V\u00e1zquez-Hern\u00e1ndez, J. E. Bandow, T. G. Pomorski, In vitro assay to evaluate cation transport of ionophores. Proteomics 22, 1\u201311 (2022).","journal-title":"Proteomics"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-29223-x"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1385\/0-89603-319-8:123"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-013-7341-z"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1111\/pbi.14340"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20945"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2009.04.013"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.23702"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00935"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-4-17"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.24829"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21367"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5251.997"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.78.2690"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpc.2009.05.011"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0506-8"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpc.2013.09.018"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21287"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4067"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp003020w"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.449071"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.328693"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540150702"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21787"},{"key":"e_1_3_5_69_2","unstructured":"J. Li V. Monje Sterol effect in saponin-induced lysis - molecular dynamics simulations set. Zenodo. https:\/\/zenodo.org\/uploads\/19961018. Deposited 1 May 2026."}],"updated-by":[{"DOI":"10.1073\/pnas.2627895123","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2523859123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:37:19Z","timestamp":1787161039000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2523859123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":69,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2026,5,12]]}},"alternative-id":["10.1073\/pnas.2523859123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2523859123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]},"assertion":[{"value":"2025-08-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2523859123"}}