HRS-WASH axis governs actin-mediated endosomal recycling and cell invasion.
HRS-WASH axis governs actin-mediated endosomal recycling and cell invasion.
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DOI：
10.1083/jcb.201710051
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发表时间：
2018-07-02
期刊：
影响因子：
--
通讯作者：
Zech T
中科院分区：
文献类型：
--
作者：
MacDonald E;Brown L;Selvais A;Liu H;Waring T;Newman D;Bithell J;Grimes D;Urbé S;Clague MJ;Zech T
ESCRT-0组分HRS和肌动蛋白聚合因子WASH位于邻近的内体结构域。MacDonald等人表明，HRS控制WASH定位和依赖WASH的跨膜货物的回收。因此，货物与内体肌动蛋白的结合作为分选信号来对抗泛素介导的降解。分选内体中的跨膜蛋白要么被回收到它们的起始点，要么被溶酶体降解。溶酶体分选是通过泛素化跨膜蛋白与运输所需的内体分选复合物（ESCRT）机制的相互作用介导的。在这项研究中，我们揭示了ESCRT-0成分肝细胞生长因子调节酪氨酸激酶底物（HRS）在促进跨膜蛋白的组成性再循环中的另一种作用。我们发现肌动蛋白成核因子wiscot - aldrich综合征蛋白和SCAR同源物（WASH）的内体定位需要HRS，它占据相邻的内体亚结构域。HRS的消耗导致表皮生长因子受体和基质金属蛋白酶MT1-MMP的组成性循环缺陷，导致它们在内部区室中积累。我们证明了有效的再循环需要与内体肌动蛋白的直接相互作用，并使用嵌合转铁蛋白受体运输的模型系统来证明肌动蛋白结合基序可以抵消溶酶体分选的泛素信号。癌细胞利用定向受体循环来实现侵袭性迁移。因此，取消HRS和肌动蛋白依赖的MT1-MMP循环会导致基质降解缺陷和三阴性乳腺癌细胞的侵袭。
ESCRT-0 component HRS and actin polymerization factor WASH reside in adjacent endosomal domains. MacDonald et al. show that HRS controls WASH localization and recycling of WASH-dependent transmembrane cargo. Cargo binding to endosomal actin thus acts as sorting signal to oppose ubiquitin-mediated degradation. Transmembrane proteins in the sorting endosome are either recycled to their point of origin or destined for lysosomal degradation. Lysosomal sorting is mediated by interaction of ubiquitylated transmembrane proteins with the endosomal sorting complex required for transport (ESCRT) machinery. In this study, we uncover an alternative role for the ESCRT-0 component hepatocyte growth factor–regulated tyrosine kinase substrate (HRS) in promoting the constitutive recycling of transmembrane proteins. We find that endosomal localization of the actin nucleating factor Wiscott-Aldrich syndrome protein and SCAR homologue (WASH) requires HRS, which occupies adjacent endosomal subdomains. Depletion of HRS results in defective constitutive recycling of epidermal growth factor receptor and the matrix metalloproteinase MT1–MMP, leading to their accumulation in internal compartments. We show that direct interactions with endosomal actin are required for efficient recycling and use a model system of chimeric transferrin receptor trafficking to show that an actin-binding motif can counteract an ubiquitin signal for lysosomal sorting. Directed receptor recycling is used by cancer cells to achieve invasive migration. Accordingly, abrogating HRS- and actin-dependent MT1-MMP recycling results in defective matrix degradation and invasion of triple-negative breast cancer cells.
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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影响因子：
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