Kazan, J.M.Desrochers, G.Martin, C.E.Jeong, H.Kharitidi, D.Apaja, P.M.Roldan, A.St. Denis, N.Gingras, A.-C.Lukacs, G.L.Pause, A.2025-07-212025-07-212021iScience, 2021; 24(11):103274-1-103274-272589-00422589-0042https://hdl.handle.net/2440/146201Internalized and ubiquitinated signaling receptors are silenced by their intraluminal budding into multivesicular bodies aided by the endosomal sorting complexes required for transport (ESCRT) machinery. HD-PTP, an ESCRT protein, forms complexes with ESCRT-0, -I and -III proteins, and binds to Endofin, a FYVE-domain protein confined to endosomes with poorly understood roles. Using proximity biotinylation, we showed that Endofin forms a complex with ESCRT constituents and Endofin depletion increased integrin a5-and EGF-receptor plasma membrane density and stability by hampering their lysosomal delivery. This coincided with sustained receptor signaling and increased cell migration. Complementation of Endofin- or HD-PTP-depleted cells with wild-type Endofin or HD-PTP, but not with mutants harboring impaired Endofin/HD-PTP association or cytosolic Endofin, restored EGFR lysosomal delivery. Endofin also promoted Hrs indirect interaction with HD-PTP. Jointly, our results indicate that Endofin is required for HD-PTP and ESCRT-0 interdependent sorting of ubiquitinated transmembrane cargoes to ensure efficient receptor desensitization and lysosomal delivery.en© 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).signaling receptors; endosomal sorting complexes required for transport (ESCRT) machinery; HD-PTP; ESCRT-0, -I, -III proteins; Endofin; endosomes; cell migration; cellsJournal article10.1016/j.isci.2021.103274592280Apaja, P.M. [0000-0002-1622-2332]