期刊
CURRENT BIOLOGY
卷 23, 期 6, 页码 453-461出版社
CELL PRESS
DOI: 10.1016/j.cub.2013.02.033
关键词
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资金
- Biotechnology and Biological Sciences Research Council [BB/I012109/1] Funding Source: Medline
- Medical Research Council [G0701141 and, G0701140, G0900930] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BB/I012109/1] Funding Source: researchfish
- Medical Research Council [G0900930, G0701140] Funding Source: researchfish
- BBSRC [BB/I012109/1] Funding Source: UKRI
- MRC [G0900930, G0701140] Funding Source: UKRI
Background: Sorting ubiquitinated epidermal growth factor receptor (EGFR) to the intralumenal vesicles of the multive-sicular 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.
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