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Dedicated proteins known as fusogens are responsible for mediating membrane fusion. However, until recently, these proteins either remained unidentified or were poorly understood at the mechanistic level. Here, we review how fusogens surmount multiple energy barriers to mediate cell-cell fusion. We describe how early preparatory steps bring membranes to a distance of \u223c10\u2005nm, while fusogens act in the final approach between membranes. The mechanical force exerted by cell fusogens and the accompanying lipidic rearrangements constitute the hallmarks of cell-cell fusion. Finally, we discuss the relationship between viral and eukaryotic fusogens, highlight a classification scheme regrouping a superfamily of fusogens called Fusexins, and propose new questions and avenues of enquiry.<\/jats:p>","DOI":"10.1242\/dev.155523","type":"journal-article","created":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T12:20:24Z","timestamp":1513599624000},"page":"4481-4495","source":"Crossref","is-referenced-by-count":199,"title":["The hallmarks of cell-cell fusion"],"prefix":"10.1242","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-9708","authenticated-orcid":false,"given":"Javier M.","family":"Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Max Planck Institute of Molecular Physiology 1 Department of Structural Biochemistry , , D-44227 Dortmund , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0411-4182","authenticated-orcid":false,"given":"Benjamin","family":"Podbilewicz","sequence":"additional","affiliation":[{"name":"Technion \u2013 Israel Institute of Technology 2 Department of Biology , , Haifa 32000 , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2024061215574653900_DEV155523C1","doi-asserted-by":"publisher","first-page":"3545","DOI":"10.1242\/dev.068148","article-title":"Notch and Ras promote sequential steps of excretory tube development in C. elegans","volume":"138","author":"Abdus-Saboor","year":"2011","journal-title":"Development"},{"key":"2024061215574653900_DEV155523C2","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1242\/dev.068353","article-title":"Myoblast fusion: lessons from flies and mice","volume":"139","author":"Abmayr","year":"2012","journal-title":"Development"},{"key":"2024061215574653900_DEV155523C3","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.tig.2013.01.011","article-title":"Genetic basis of cell-cell fusion mechanisms","volume":"29","author":"Aguilar","year":"2013","journal-title":"Trends Genet."},{"key":"2024061215574653900_DEV155523C4","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/B978-0-12-385891-7.00009-X","article-title":"Eukaryotic cell-cell fusion families","volume":"68","author":"Avinoam","year":"2011","journal-title":"Curr. 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