Abstract
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.
Original language | English |
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Article number | 103274 |
Number of pages | 27 |
Journal | iScience |
Volume | 24 |
Issue number | 11 |
DOIs | |
Publication status | Published - 19 Nov 2021 |
Externally published | Yes |
Keywords
- Biological sciences
- Cell biology
- Molecular biology
- Endofin
- HD-PTP
- ESCRT-0
- endosomal sorting
- ubiquitinated transmembrane cargoes
- endosomes
- receptor signaling