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

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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Article number103274
Number of pages27
JournaliScience
Volume24
Issue number11
DOIs
Publication statusPublished - 19 Nov 2021
Externally publishedYes

Keywords

  • Biological sciences
  • Cell biology
  • Molecular biology
  • Endofin
  • HD-PTP
  • ESCRT-0
  • endosomal sorting
  • ubiquitinated transmembrane cargoes
  • endosomes
  • receptor signaling

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