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We confirmed that lipid scrambling through the scramblase TMEM16F is essential for chemically induced membrane blebbing across cell types, with the kinetics of PS exposure being tightly coupled to the kinetics of bleb formation. Measurement of lipid packing with environment-sensitive probes revealed that lipid scrambling changes the physical properties of the PM, reducing lipid packing and facilitating the bilayer bending required for bleb formation. Accordingly, reducing lipid packing of the PM through cholesterol extraction, elevated temperature, or treatment with biological amphiphiles promoted blebbing in the absence of TMEM16F. Consistent with these cellular observations, blebbing in\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    embryos measured via EV production was significantly reduced by depleting the TMEM16-homolog ANOH-2. Our findings suggest that changing membrane biophysical properties by lipid scrambling is an important contributor to the formation of blebs and EVs and potentially other cellular processes involving PM deformation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2417145122","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T15:08:54Z","timestamp":1746457734000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Loss of lipid asymmetry facilitates plasma membrane blebbing by decreasing membrane lipid packing"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8704-2814","authenticated-orcid":false,"given":"Hong-Yin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, Center for Membrane and Cell Physiology, University of Virginia","place":["Charlottesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0314-1353","authenticated-orcid":false,"given":"Alissa","family":"Rumin","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Biophysics Program, Department of Biological Sciences, University of Denver","place":["Denver"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4366-2242","authenticated-orcid":false,"given":"Milka","family":"Doktorova","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, Center for Membrane and Cell Physiology, University of Virginia","place":["Charlottesville"]},{"name":"Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University","place":["Solna, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9987-5582","authenticated-orcid":false,"given":"Daryna","family":"Sputay","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, Center for Membrane and Cell Physiology, University of Virginia","place":["Charlottesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3235-0852","authenticated-orcid":false,"given":"Sze Ham","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, Center for Membrane and Cell Physiology, University of Virginia","place":["Charlottesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9826-4132","authenticated-orcid":false,"given":"Ann M.","family":"Wehman","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Biophysics Program, Department of Biological Sciences, University of Denver","place":["Denver"]},{"name":"Department of Biochemistry and Biophysics, Texas A&M University","place":["College Station"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2234-3683","authenticated-orcid":false,"given":"Kandice R.","family":"Levental","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, Center for Membrane and Cell Physiology, University of Virginia","place":["Charlottesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1206-9545","authenticated-orcid":false,"given":"Ilya","family":"Levental","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, Center for Membrane and Cell Physiology, University of Virginia","place":["Charlottesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00604-z"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-020-00688-0"},{"key":"e_1_3_4_3_2","unstructured":"M. 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