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Endofin是泛素化跨膜货物的HD-PTP和ESCRT-0相互依赖的内体分选所必需的。

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

作者信息

Kazan Jalal M, Desrochers Guillaume, Martin Claire E, Jeong Hyeonju, Kharitidi Dmitri, Apaja Pirjo M, Roldan Ariel, St Denis Nicole, Gingras Anne-Claude, Lukacs Gergely L, Pause Arnim

机构信息

Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.

Biochemistry Department, McGill University, Montreal, QC H3G 1Y6, Canada.

出版信息

iScience. 2021 Oct 14;24(11):103274. doi: 10.1016/j.isci.2021.103274. eCollection 2021 Nov 19.

DOI:10.1016/j.isci.2021.103274
PMID:34761192
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8567383/
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.

摘要

内化和泛素化的信号受体通过腔内出芽进入多囊泡体而沉默，这一过程由转运所需的内体分选复合物（ESCRT）机制辅助。ESCRT蛋白HD-PTP与ESCRT-0、-I和-III蛋白形成复合物，并与Endofin结合，Endofin是一种局限于内体的FYVE结构域蛋白，其作用尚不清楚。通过邻近生物素化，我们发现Endofin与ESCRT成分形成复合物，Endofin的缺失通过阻碍整合素α5和表皮生长因子受体（EGF受体）向溶酶体的转运，增加了它们在质膜上的密度和稳定性。这与持续的受体信号传导和细胞迁移增加相一致。用野生型Endofin或HD-PTP对Endofin或HD-PTP缺失的细胞进行互补，但不能用Endofin/HD-PTP结合受损的突变体或胞质Endofin进行互补，可恢复EGFR向溶酶体的转运。Endofin还促进了Hrs与HD-PTP的间接相互作用。总之，我们的结果表明，Endofin是HD-PTP和ESCRT-0将泛素化跨膜货物进行相互依赖分选所必需的，以确保有效的受体脱敏和向溶酶体的转运。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/2469e3e2146f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/1f67f79cd5f8/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/6eb9bb46144c/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/b12607b2b0bd/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/4cf5e51eeb3a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/ab75bef5c49e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/227ca38b7e34/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/2469e3e2146f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/1f67f79cd5f8/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/6eb9bb46144c/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/b12607b2b0bd/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/4cf5e51eeb3a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/ab75bef5c49e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/227ca38b7e34/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768e/8567383/2469e3e2146f/gr6.jpg

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