Sec14L6 Is a Phosphoinositide Transporter That Regulates Phosphoinositide Homeostasis and Biogenesis of Lipid Droplet

Sec14L6 Is a Phosphoinositide Transporter That Regulates Phosphoinositide Homeostasis and Biogenesis of Lipid Droplet | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Sec14L6 Is a Phosphoinositide Transporter That Regulates Phosphoinositide Homeostasis and Biogenesis of Lipid Droplet Weike Ji, Tiantian zhou, xuewen hu, Juan Xiong, Yuanjiao Du This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6888955/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Lipid droplets (LDs) are evolutionarily conserved organelles crucial for cellular metabolism. Their biogenesis and growth occur in the endoplasmic reticulum (ER) and rely on lipid transfer between the ER and LDs. However, the molecular mechanisms remain poorly understood. In this study, we identified Sec14L6, a unique Sec14 protein family member, as a lipid transporter that regulates phosphoinositide homeostasis and biogenesis of LDs, and is required for the differentiation of adipose-derived mesenchymal stem cells. Sec14L6 directly binds to ACSL3, a known LD biogenesis factor, which facilitates the association of Sec14L6 with LD surface. Furthermore, we identify PGRMC1, an ER membrane protein, as an adaptor that recruits Sec14L6 to the ER, specifying a role for Sec14L6 at ER-LD interface. Targeted lipidomics revealed profound dysregulation of PIP homeostasis: residual LDs from Sec14L6-KO cells exhibited aberrant accumulation of PI4P and PI(4,5)P2, concomitant with a reduction of these PIPs within the ER compartment. In vitro assays demonstrate that Sec14L6 preferentially transports phosphoinositide-4-phosphate (PI4P) and PI(4,5)P2. Sec14L6 knockout (KO) severely impaired nascent LD formation, a defect rescued by wild-type Sec14L6 but not by lipid-transfer-deficient mutants. Our study identified Sec14L6 as a new factor that regulates PIP homeostasis and biogenesis of LDs via lipid transfer at ER-LD interface. Biological sciences/Cell biology/Organelles/Endoplasmic reticulum Biological sciences/Cell biology/Membrane trafficking Full Text Additional Declarations There is NO Competing Interest. Supplementary Files video1.mp4 video-1 Cite Share Download PDF Status: Published Journal Publication published 26 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6888955","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":472500165,"identity":"bf0a7df8-76ea-45c3-8ce7-273a1d5616fa","order_by":0,"name":"Weike Ji","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYFACxmYgwcbDxt58/MMHAxs74rXw8RxLY5xRkJZMjDXMYFJOIseMmefDIcYGQuoNjjc3G3xg4JNhk0hLe2xjcICZgf3w0Q14tZw52Jw4A+QXnsfHjXMM7vAx8KSl3cCnxexGYvNhHrD30xKkcwyeMTNI8Jjh13L/YfPhPyAtDDkG0hYGhxkbCGq5wdicDA5kjhwzaQZitNifSWw27AH75ViyYY9BWjIbIb9Ith9/LPGD4Zi9fHvzwQc//tjY8bMfPoZXCxgw/juG4LARVA4BNUSqGwWjYBSMghEJAHvgRcRBDesuAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-1788-0879","institution":"Huazhong University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Weike","middleName":"","lastName":"Ji","suffix":""},{"id":472500166,"identity":"c433adcb-1316-4115-8698-903c981f275f","order_by":1,"name":"Tiantian zhou","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Tiantian","middleName":"","lastName":"zhou","suffix":""},{"id":472500167,"identity":"3979cf88-c328-46b9-b771-359471ca861c","order_by":2,"name":"xuewen hu","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"xuewen","middleName":"","lastName":"hu","suffix":""},{"id":472500168,"identity":"9fb28a5f-74f3-444e-80df-0fd00cdce6b6","order_by":3,"name":"Juan Xiong","email":"","orcid":"https://orcid.org/0000-0002-3005-0274","institution":"Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Xiong","suffix":""},{"id":472500169,"identity":"bd1a9d7a-f01b-4a40-82bc-4d735a6ce19e","order_by":4,"name":"Yuanjiao Du","email":"","orcid":"","institution":"Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Yuanjiao","middleName":"","lastName":"Du","suffix":""}],"badges":[],"createdAt":"2025-06-13 14:16:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6888955/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6888955/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-65540-2","type":"published","date":"2025-11-26T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":96885652,"identity":"8dba849d-aec4-40c9-9158-2e081c7de8e9","added_by":"auto","created_at":"2025-11-27 08:09:14","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":13488707,"visible":true,"origin":"","legend":"Article File","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6888955/v1_covered_ccbb8940-6971-465c-a17b-39706471954c.pdf"},{"id":84881557,"identity":"d2d7c16e-cb31-4266-81a3-2b4d81493cb2","added_by":"auto","created_at":"2025-06-18 10:59:20","extension":"mp4","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":152808,"visible":true,"origin":"","legend":"video-1","description":"","filename":"video1.mp4","url":"https://assets-eu.researchsquare.com/files/rs-6888955/v1/dc1bc702f84dd3ff6a24a905.mp4"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Sec14L6 Is a Phosphoinositide Transporter That Regulates Phosphoinositide Homeostasis and Biogenesis of Lipid Droplet","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6888955/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6888955/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Lipid droplets (LDs) are evolutionarily conserved organelles crucial for cellular metabolism. Their biogenesis and growth occur in the endoplasmic reticulum (ER) and rely on lipid transfer between the ER and LDs. However, the molecular mechanisms remain poorly understood. In this study, we identified Sec14L6, a unique Sec14 protein family member, as a lipid transporter that regulates phosphoinositide homeostasis and biogenesis of LDs, and is required for the differentiation of adipose-derived mesenchymal stem cells. Sec14L6 directly binds to ACSL3, a known LD biogenesis factor, which facilitates the association of Sec14L6 with LD surface. Furthermore, we identify PGRMC1, an ER membrane protein, as an adaptor that recruits Sec14L6 to the ER, specifying a role for Sec14L6 at ER-LD interface. Targeted lipidomics revealed profound dysregulation of PIP homeostasis: residual LDs from Sec14L6-KO cells exhibited aberrant accumulation of PI4P and PI(4,5)P2, concomitant with a reduction of these PIPs within the ER compartment. In vitro assays demonstrate that Sec14L6 preferentially transports phosphoinositide-4-phosphate (PI4P) and PI(4,5)P2. Sec14L6 knockout (KO) severely impaired nascent LD formation, a defect rescued by wild-type Sec14L6 but not by lipid-transfer-deficient mutants. Our study identified Sec14L6 as a new factor that regulates PIP homeostasis and biogenesis of LDs via lipid transfer at ER-LD interface.","manuscriptTitle":"Sec14L6 Is a Phosphoinositide Transporter That Regulates Phosphoinositide Homeostasis and Biogenesis of Lipid Droplet","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 10:51:16","doi":"10.21203/rs.3.rs-6888955/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ff743c15-5a9b-456d-84d5-9a1d0a41a04c","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":50177229,"name":"Biological sciences/Cell biology/Organelles/Endoplasmic reticulum"},{"id":50177230,"name":"Biological sciences/Cell biology/Membrane trafficking"}],"tags":[],"updatedAt":"2025-11-27T08:09:04+00:00","versionOfRecord":{"articleIdentity":"rs-6888955","link":"https://doi.org/10.1038/s41467-025-65540-2","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-11-26 05:00:00","publishedOnDateReadable":"November 26th, 2025"},"versionCreatedAt":"2025-06-18 10:51:16","video":"","vorDoi":"10.1038/s41467-025-65540-2","vorDoiUrl":"https://doi.org/10.1038/s41467-025-65540-2","workflowStages":[]},"version":"v1","identity":"rs-6888955","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6888955","identity":"rs-6888955","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}