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Recruitment of UBPY and ESCRT Exchange Drive HD-PTP-Dependent Sorting of EGFR to the MVB

Ali, Nazim; Zhang, Ling; Taylor, Sandra; Mironov, Alex; Urbé, Sylvie; Woodman, Philip

Recruitment of UBPY and ESCRT Exchange Drive HD-PTP-Dependent Sorting of EGFR to the MVB Thumbnail


Authors

Nazim Ali

Ling Zhang

Sandra Taylor

Alex Mironov

Sylvie Urbé

Philip Woodman



Abstract

Background
Sorting ubiquitinated epidermal growth factor receptor (EGFR) to the intralumenal vesicles of the multivesicular body requires the coordinated action of several ESCRT complexes. A central question is how EGFR transits vectorially from early, ubiquitin-binding ESCRTs to the final complex, ESCRT-III, such that cargo sequestration is coupled with intralumenal vesicle formation.
Results
We show that the ESCRT accessory protein HD-PTP/PTPN23 associates with EGFR and combines with the deubiquitinating enzyme UBPY/USP8 to transfer EGFR from ESCRT-0 to ESCRT-III and drive EGFR sorting to intralumenal vesicles. HD-PTP binds ESCRT-0 via two interactions with the STAM2 subunit. First, the HD-PTP Bro1 domain binds the core domain of STAM2. This is competed by the ESCRT-III subunit CHMP4B, which binds an overlapping site on HD-PTP Bro1. Second, a proline-rich peptide in HD-PTP binds the SH3 domain of STAM2. Similar proline-rich peptides on UBPY also bind STAM2 SH3 to facilitate EGFR deubiquitination. Hence, locally recruited UBPY would be expected to compete with HD-PTP for STAM2 binding at this second site. Indeed, we show that HD-PTP recruits UBPY to EGFR. Association of UBPY with HD-PTP involves UBPY interacting with HD-PTP-bound CHMP4B, as well as additional interaction(s) between UBPY and HD-PTP.
Conclusions
This study identifies HD-PTP as a central coordinator of the ESCRT pathway for EGFR. Based on these studies, we propose a model whereby the concerted recruitment of CHMP4B and UBPY to HD-PTP and the engagement of UBPY by STAM2 displaces ESCRT-0 from HD-PTP, deubiquitinates EGFR, and releases ESCRT-0 from cargo in favor of ESCRT-III.

Acceptance Date Feb 14, 2013
Online Publication Date Mar 7, 2013
Publication Date Mar 18, 2013
Publicly Available Date Mar 28, 2024
Journal Current Biology
Print ISSN 0960-9822
Publisher Elsevier
Volume 23
Issue 6
Pages 453 - 461
DOI https://doi.org/10.1016/j.cub.2013.02.033
Publisher URL https://www.cell.com/current-biology/fulltext/S0960-9822(13)00204-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0960982213002042%3Fshowall%3Dtrue#relatedArticles

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