USP8 Controls the Trafficking and Sorting of Lysosomal Enzymes
USP8 Controls the Trafficking and Sorting of Lysosomal Enzymes
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DOI：
10.1111/tra.12180
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发表时间：
2014-08-01
期刊：
影响因子：
4.5
通讯作者：
Clague, Michael J.
中科院分区：
文献类型：
--
作者：
MacDonald, Ewan;Urbe, Sylvie;Clague, Michael J.
内体去泛素化酶 USP8 对内体形态和组织具有深远的影响。之前的报告提出了受体下调（Frizzled、Smoothened）中的积极作用（EGFR、MET）和消极作用。在这里，我们报告了 USP8 对 ci-M6PR 在分选内体和生物合成途径之间依赖逆转录酶的穿梭的额外影响。 USP8 的耗尽导致 ci-M6PR 从跨高尔基体网络 (TGN) 稳态重新分布到内体区室。因此，我们观察到溶酶体酶的分类存在缺陷，这可以通过分泌到培养基中的未加工的组织蛋白酶 D 的水平增加来证明。受体的正常分布可以通过 siRNA 抗性 USP8 的表达来恢复，但不能通过催化失活突变体或截短形式来恢复，因为缺乏内体定位所需的 MIT 结构域。我们认为 USP8 耗竭的影响可能反映了与逆转录体成分 Vps35 和 SNX1 相关的 ESCRT-0 成分的损失，同时未能有效递送溶酶体酶也可能导致观察到的受体酪氨酸激酶降解受阻。
The endosomal deubiquitylase USP8 has profound effects on endosomal morphology and organisation. Previous reports have proposed both positive (EGFR, MET) and negative roles in the down-regulation of receptors (Frizzled, Smoothened). Here we report an additional influence of USP8 on the retromer-dependent shuttling of ci-M6PR between the sorting endosome and biosynthetic pathway. Depletion of USP8 leads to a steady state redistribution of ci-M6PR from the Trans-Golgi Network (TGN) to endosomal compartments. Consequently we observe a defect in sorting of lysosomal enzymes, evidenced by increased levels of unprocessed Cathepsin D, which is secreted into the medium. The normal distribution of receptor can be restored by expression of siRNA-resistant USP8 but not by a catalytically inactive mutant or a truncated form, lacking a MIT domain required for endosomal localisation. We suggest that effects of USP8 depletion may reflect the loss of ESCRT-0 components which associate with retromer components Vps35 and SNX1, whilst failure to efficiently deliver lysosomal enzymes may also contribute to the observed block in receptor tyrosine kinase degradation.