Endofin is required for HD-PTP and ESCRT-0 interdependent endosomal sorting of ubiquitinated transmembrane cargoes

• DOI: 10.1016/j.isci.2021.103274
• Publication Date: 2021-10-14T12:05:21Z
• Authors: Jalal M. Kazan; Guillaume Desrochers; Claire E. Martin; Hyeonju Jeong; Dmitri Kharitidi; Pirjo M. Apaja; Ariel Roldan; Nicole St. Denis; Anne-Claude Gingras; Gergely L. Lukacs; Arnim Pause
• Keywords: Biological sciences; Cell biology; 0303 health sciences; 03 medical and health sciences; Molecular biology; Science; Q; Article

Internalized 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 α5-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.