Endofin is Required for HD-PTP and ESCRT-0 Interdependent Endosomal Sorting of Ubiquitinated Transmembrane Cargoes.
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(Published vresion)
Date
2021
Authors
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.
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iScience, 2021; 24(11):103274-1-103274-27
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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, and Arnim Pause
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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 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.
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© 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/).