{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T11:37:44Z","timestamp":1792755464699,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:00:00Z","timestamp":1792195200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"CIHR","doi-asserted-by":"publisher","award":["178189"],"award-info":[{"award-number":["178189"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The facultative intracellular pathogen, Listeria monocytogenes, disseminates among host cells to infect entire organs. This cellular transfer is driven through the coordination of bacterial factors that form actin-rich fingerlike listeriopod protrusions in \u201csending\u201d cells and host cell endocytosis of these large structures in \u201creceiving\u201d cells. Previous studies have demonstrated that the process that internalizes these large structures exploits both Caveolin- and Flotillin-mediated endocytosis. However, how early endocytic regulators contribute to L. monocytogenes cell-to-cell spreading remains unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Rab5a\/RIN2 (Ras and Rab interactor 2) localization was analyzed using immunofluorescence microscopy during L. monocytogenes infections in JEG-3 cells, a human choriocarcinoma cell line derived from placental trophoblastic tissue. The protein functions were then examined using transfection with wild-type and mutant constructs and siRNA-mediated knockdown approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We show that Rab5a and RIN2 are selectively enriched at L. monocytogenes invaginations, but not at listeriopods. Functional cell-to-cell spreading assays coupled with loss- and gain-of-function approaches showed that depletion or inhibition of Rab5a in the receiving cells significantly reduced bacterial dissemination, whereas expression of constitutively active Rab5a enhanced cell-to-cell spreading. Similarly, RIN2 localized to Rab5a-positive invaginations and was required for efficient cell-to-cell spreading, with RIN2 knockdowns resulting in a significant reduction in bacterial transfer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data identify Rab5a and RIN2 as key host endocytic regulators that promote L. monocytogenes dissemination.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiag515","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:52:00Z","timestamp":1792065120000},"source":"Crossref","is-referenced-by-count":0,"title":["Rab5a and RIN2 Promote\n                    <i>Listeria monocytogenes<\/i>\n                    Cell-to-Cell Spreading in JEG-3 Cells"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2349-7039","authenticated-orcid":false,"given":"Petra A","family":"McLeod","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Centre for Cell Biology, Development, and Disease (C2D2), Simon Fraser University , Burnaby, Bc ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5252-7132","authenticated-orcid":false,"given":"Peter L","family":"Beach","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Centre for Cell Biology, Development, and Disease (C2D2), Simon Fraser University , Burnaby, Bc ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6085-8860","authenticated-orcid":false,"given":"Ahmed M H","family":"Bshina","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Centre for Cell Biology, Development, and Disease (C2D2), Simon Fraser University , Burnaby, Bc ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian A","family":"Guttman","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Centre for Cell Biology, Development, and Disease (C2D2), Simon Fraser University , Burnaby, Bc ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,17]]},"reference":[{"key":"2026102306411917800_jiag515-B1","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1016\/j.febslet.2014.05.051","article-title":"A trip in the \u201cNew Microbiology\u201d with the bacterial pathogen Listeria monocytogenes","volume":"588","author":"Cossart","year":"2014","journal-title":"FEBS Lett"},{"key":"2026102306411917800_jiag515-B2","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nrmicro1413","article-title":"Listeria monocytogenes: a multifaceted model","volume":"4","author":"Hamon","year":"2006","journal-title":"Nat Rev Microbiol"},{"key":"2026102306411917800_jiag515-B3","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1083\/jcb.200205009","article-title":"The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity","volume":"158","author":"Portnoy","year":"2002","journal-title":"J Cell Biol"},{"key":"2026102306411917800_jiag515-B4","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/ncb1292","article-title":"Listeria hijacks the clathrin-dependent endocytic machinery to invade mammalian cells","volume":"7","author":"Veiga","year":"2005","journal-title":"Nat Cell Biol"},{"key":"2026102306411917800_jiag515-B5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/978-94-017-8881-6_9","article-title":"Multifaceted activity of listeriolysin O, the cholesterol-dependent cytolysin of Listeria monocytogenes","volume":"80","author":"Seveau","year":"2014","journal-title":"Subcell Biochem"},{"key":"2026102306411917800_jiag515-B6","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/978-1-4939-6673-8_11","article-title":"Assessing vacuolar escape of Listeria monocytogenes","volume":"1535","author":"Quereda","year":"2017","journal-title":"Methods Mol Biol"},{"key":"2026102306411917800_jiag515-B7","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1128\/iai.55.7.1641-1646.1987","article-title":"Purification, characterization, and toxicity of the sulfhydryl-activated hemolysin listeriolysin O from Listeria monocytogenes","volume":"55","author":"Geoffroy","year":"1987","journal-title":"Infect Immun"},{"key":"2026102306411917800_jiag515-B8","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/385265a0","article-title":"Actin polymerization is induced by Arp2\/3 protein complex at the surface of Listeria monocytogenes","volume":"385","author":"Welch","year":"1997","journal-title":"Nature"},{"key":"2026102306411917800_jiag515-B9","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/S0960-9822(01)00022-7","article-title":"Dendritic organization of actin comet tails","volume":"11","author":"Cameron","year":"2001","journal-title":"Curr Biol"},{"key":"2026102306411917800_jiag515-B10","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/0092-8674(92)90188-I","article-title":"L. monocytogenes-induced actin assembly requires the actA gene product, a surface protein","volume":"68","author":"Kocks","year":"1992","journal-title":"Cell"},{"key":"2026102306411917800_jiag515-B11","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1126\/science.281.5373.105","article-title":"Interaction of human Arp2\/3 complex and the Listeria monocytogenes ActA protein in actin filament nucleation","volume":"281","author":"Welch","year":"1998","journal-title":"Science"},{"key":"2026102306411917800_jiag515-B12","doi-asserted-by":"crossref","first-page":"20521","DOI":"10.1073\/pnas.1320155110","article-title":"Three-dimensional architecture of actin filaments in Listeria monocytogenes comet tails","volume":"110","author":"Jasnin","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026102306411917800_jiag515-B13","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1083\/jcb.109.4.1597","article-title":"Actin filaments and the growth, movement, and spread of the intracellular bacterial parasite, Listeria monocytogenes","volume":"109","author":"Tilney","year":"1989","journal-title":"J Cell Biol"},{"key":"2026102306411917800_jiag515-B14","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1091\/mbc.E19-04-0197","article-title":"RNAi screen reveals a role for PACSIN2 and caveolins during bacterial cell-to-cell spread","volume":"30","author":"Sanderlin","year":"2019","journal-title":"Mol Biol Cell"},{"key":"2026102306411917800_jiag515-B15","doi-asserted-by":"crossref","first-page":"e778","DOI":"10.1093\/infdis\/jiaf452","article-title":"Role of flotillin-1 in Listeria monocytogenes cell-to-cell spreading","volume":"232","author":"McLeod","year":"2025","journal-title":"J Infect Dis"},{"key":"2026102306411917800_jiag515-B16","doi-asserted-by":"crossref","first-page":"e02857-19","DOI":"10.1128\/mBio.02857-19","article-title":"Listeria monocytogenes exploits host caveolin for cell-to-cell spreading","volume":"11","author":"Dhanda","year":"2020","journal-title":"mBio"},{"key":"2026102306411917800_jiag515-B17","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1146\/annurev.biochem.78.081307.110540","article-title":"Mechanisms of endocytosis","volume":"78","author":"Doherty","year":"2009","journal-title":"Annu Rev Biochem"},{"key":"2026102306411917800_jiag515-B18","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1083\/jcb.143.1.81","article-title":"Sorting mechanisms regulating membrane protein traffic in the apical transcytotic pathway of polarized MDCK cells","volume":"143","author":"Gibson","year":"1998","journal-title":"J Cell Biol"},{"key":"2026102306411917800_jiag515-B19","doi-asserted-by":"crossref","first-page":"4186308","DOI":"10.1155\/2020\/4186308","article-title":"The emerging role of Rab5 in membrane receptor trafficking and signaling pathways","volume":"2020","author":"Yuan","year":"2020","journal-title":"Biochem Res Int"},{"key":"2026102306411917800_jiag515-B20","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1242\/jcs.00289","article-title":"Real-time analysis of clathrin-mediated endocytosis during cell migration","volume":"116","author":"Rappoport","year":"2003","journal-title":"J Cell Sci"},{"key":"2026102306411917800_jiag515-B21","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/0092-8674(91)90316-Q","article-title":"Rab5 controls early endosome fusion in vitro","volume":"64","author":"Gorvel","year":"1991","journal-title":"Cell"},{"key":"2026102306411917800_jiag515-B22","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/35052055","article-title":"Rab proteins as membrane organizers","volume":"2","author":"Zerial","year":"2001","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026102306411917800_jiag515-B23","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1002\/j.1460-2075.1994.tb06381.x","article-title":"Inhibition of Rab5 GTPase activity stimulates membrane fusion in endocytosis","volume":"13","author":"Stenmark","year":"1994","journal-title":"EMBO J"},{"key":"2026102306411917800_jiag515-B24","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/28879","article-title":"EEA1 links PI(3)K function to Rab5 regulation of endosome fusion","volume":"394","author":"Simonsen","year":"1998","journal-title":"Nature"},{"key":"2026102306411917800_jiag515-B25","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1038\/cr.2012.110","article-title":"The R-Ras\/RIN2\/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling","volume":"22","author":"Sandri","year":"2012","journal-title":"Cell Res"},{"key":"2026102306411917800_jiag515-B26","doi-asserted-by":"crossref","first-page":"18720","DOI":"10.1016\/S0021-9258(17)32224-X","article-title":"Rab5, an early acting endosomal GTPase, supports in vitro endosome fusion without GTP hydrolysis","volume":"269","author":"Barbieri","year":"1994","journal-title":"J Biol Chem"},{"key":"2026102306411917800_jiag515-B27","doi-asserted-by":"crossref","first-page":"3412","DOI":"10.1074\/jbc.M106276200","article-title":"A novel binding protein composed of homophilic tetramer exhibits unique properties for the small GTPase Rab5","volume":"277","author":"Saito","year":"2002","journal-title":"J Biol Chem"},{"key":"2026102306411917800_jiag515-B28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.tcb.2005.11.001","article-title":"Vps9 domain-containing proteins: activators of Rab5 GTPases from yeast to neurons","volume":"16","author":"Carney","year":"2006","journal-title":"Trends Cell Biol"},{"key":"2026102306411917800_jiag515-B29","doi-asserted-by":"crossref","first-page":"10598","DOI":"10.1074\/jbc.M510531200","article-title":"Involvement of the Ras-Ras-activated Rab5 guanine nucleotide exchange factor RIN2-Rab5a pathway in the hepatocyte growth factor-induced endocytosis of E-cadherin","volume":"281","author":"Kimura","year":"2006","journal-title":"J Biol Chem"},{"key":"2026102306411917800_jiag515-B30","doi-asserted-by":"crossref","first-page":"e30575","DOI":"10.1371\/journal.pone.0030575","article-title":"RINL, guanine nucleotide exchange factor Rab5-subfamily, is involved in the EphA8-degradation pathway with odin","volume":"7","author":"Kajiho","year":"2012","journal-title":"PLoS One"},{"key":"2026102306411917800_jiag515-B31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.bbrc.2008.10.172","article-title":"Caveolin-1 activates Rab5 and enhances endocytosis through direct interaction","volume":"378","author":"Hagiwara","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"2026102306411917800_jiag515-B32","doi-asserted-by":"crossref","first-page":"4392","DOI":"10.1038\/s41467-019-12352-w","article-title":"Flotillins promote T cell receptor sorting through a fast Rab5-Rab11 endocytic recycling axis","volume":"10","author":"Redpath","year":"2019","journal-title":"Nat Commun"},{"key":"2026102306411917800_jiag515-B33","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/0092-8674(95)90120-5","article-title":"Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion","volume":"83","author":"Stenmark","year":"1995","journal-title":"Cell"},{"key":"2026102306411917800_jiag515-B34","doi-asserted-by":"crossref","first-page":"962","DOI":"10.3390\/cells11060962","article-title":"Early endosomal Vps34-derived phosphatidylinositol-3-phosphate is indispensable for the biogenesis of the endosomal recycling compartment","volume":"11","author":"Marceli\u0107","year":"2022","journal-title":"Cells"},{"key":"2026102306411917800_jiag515-B35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20071427","article-title":"The regulation and function of class III PI3Ks: novel roles for Vps34","volume":"410","author":"Backer","year":"2008","journal-title":"Biochem J"},{"key":"2026102306411917800_jiag515-B36","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3389\/fcimb.2020.00419","article-title":"The Salmonella effector SseK3 targets small Rab GTPases","volume":"10","author":"Gan","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"key":"2026102306411917800_jiag515-B37","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1083\/jcb.200804131","article-title":"Sopb promotes phosphatidylinositol 3-phosphate formation on Salmonella vacuoles by recruiting Rab5 and Vps34","volume":"182","author":"Mallo","year":"2008","journal-title":"J Cell Biol"},{"key":"2026102306411917800_jiag515-B38","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/21541248.2017.1332506","article-title":"Subversion of RAB5-regulated autophagy by the intracellular pathogen Ehrlichia chaffeensis","volume":"10","author":"Rikihisa","year":"2019","journal-title":"Small GTPases"},{"key":"2026102306411917800_jiag515-B39","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1080\/21541248.2016.1240494","article-title":"Diverted recycling-Shigella subversion of Rabs","volume":"9","author":"L\u00f3pez-Montero","year":"2018","journal-title":"Small GTPases"},{"key":"2026102306411917800_jiag515-B40","doi-asserted-by":"crossref","first-page":"219","DOI":"10.3389\/fimmu.2015.00219","article-title":"Shigella manipulates host immune responses by delivering effector proteins with specific roles","volume":"6","author":"Ashida","year":"2015","journal-title":"Front Immunol"},{"key":"2026102306411917800_jiag515-B41","doi-asserted-by":"crossref","first-page":"11459","DOI":"10.1074\/jbc.274.17.11459","article-title":"Increased expression of Rab5a correlates directly with accelerated maturation of Listeria monocytogenes phagosomes","volume":"274","author":"Alvarez-Dominguez","year":"1999","journal-title":"J Biol Chem"},{"key":"2026102306411917800_jiag515-B42","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1111\/j.1600-0854.2005.00265.x","article-title":"Inhibition of Rab5a exchange activity is a key step for Listeria monocytogenes survival","volume":"6","author":"Prada-Delgado","year":"2005","journal-title":"Traffic"},{"key":"2026102306411917800_jiag515-B43","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/j.1600-0854.2007.00683.x","article-title":"Characterization of a Listeria monocytogenes protein interfering with Rab5a","volume":"9","author":"Alvarez-Dominguez","year":"2008","journal-title":"Traffic"},{"key":"2026102306411917800_jiag515-B44","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/j.1462-5822.2005.00604.x","article-title":"Cytolysin-dependent delay of vacuole maturation in macrophages infected with Listeria monocytogenes","volume":"8","author":"Henry","year":"2006","journal-title":"Cell Microbiol"},{"key":"2026102306411917800_jiag515-B45","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1111\/tra.12204","article-title":"The RAB5-GEF function of RIN1 regulates multiple steps during Listeria monocytogenes infection","volume":"15","author":"Balaji","year":"2014","journal-title":"Traffic"},{"key":"2026102306411917800_jiag515-B46","doi-asserted-by":"crossref","first-page":"e912","DOI":"10.1093\/infdis\/jiaf063","article-title":"Characterization of c-Src during Listeria monocytogenes cell-to-cell spreading","volume":"231","author":"McLeod","year":"2025","journal-title":"J Infect Dis"},{"key":"2026102306411917800_jiag515-B47","doi-asserted-by":"crossref","first-page":"29182","DOI":"10.1074\/jbc.271.46.29182","article-title":"Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases","volume":"271","author":"Li","year":"1996","journal-title":"J Biol Chem"},{"key":"2026102306411917800_jiag515-B48","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/mc.20414","article-title":"Activated K-RAS increases polyamine uptake in human colon cancer cells through modulation of caveolar endocytosis","volume":"47","author":"Roy","year":"2008","journal-title":"Molecular Carcinogenesis"},{"key":"2026102306411917800_jiag515-B49","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/370527a0","article-title":"Phosphatidylinositol-3-OH kinase as a direct target of Ras","volume":"370","author":"Rodriguez-Viciana","year":"1994","journal-title":"Nature"},{"key":"2026102306411917800_jiag515-B50","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1158\/0008-5472.CAN-11-3078","article-title":"p120RasGAP-mediated activation of c-Src is critical for oncogenic Ras to induce tumor invasion","volume":"72","author":"Chan","year":"2012","journal-title":"Cancer Research"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiag515\/72066478\/jiag515.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiag515\/72066478\/jiag515.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T10:41:33Z","timestamp":1792752093000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/advance-article\/doi\/10.1093\/infdis\/jiag515\/8935268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,17]]},"references-count":50,"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiag515","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,17]]},"article-number":"jiag515"}}