Ubiquitination and dynactin regulate TMEPAI lysosomal trafficking.
Ubiquitination and dynactin regulate TMEPAI lysosomal trafficking.
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泛素化和动力蛋白调节 TMEPAI 溶酶体运输
DOI：
10.1038/srep42668
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发表时间：
2017-02-20
影响因子：
4.6
通讯作者：
Diao A
中科院分区：
文献类型：
--
作者：
Luo S;Jing L;Zhao T;Li Y;Liu Z;Diao A
据报道，跨膜前列腺雄激素诱导蛋白（TMEPAI）在各种肿瘤细胞中升高，定位于溶酶体并促进溶酶体稳定性。然而，TMEPAI运输至溶酶体的分子机制尚不清楚。在这里，我们报告，网格蛋白和CI-M6 PR介导TMEPAI运输从高尔基体直接进入内-溶酶体途径。TMEPAI在其C-末端区域被泛素化，并且TMEPAI的泛素化修饰是其溶酶体运输的信号。此外，TMEPAI结合其溶酶体转运所需的泛素结合蛋白Hrs和STAM。此外，TMEPAI与dynactin尖端复合物亚基dynactin 5和dynactin 6相互作用。aa 132-155结构域对于特异性TMEPAI结合是必需的，并且该结合位点的缺失导致TMEPAI错误运输至质膜。这些结果揭示了TMEPAI向溶酶体转运的调控途径和机制，有助于进一步了解TMEPAI在肿瘤发生中的作用。
The transmembrane prostate androgen-induced protein (TMEPAI) has been reported to be elevated in various tumor cells, is localized to the lysosome and promotes lysosome stability. The molecular mechanism of TMEPAI trafficking however to the lysosome is unknown. Here we report that clathrin and CI-M6PR mediate TMEPAI transport from the Golgi directly into the endo-lysosomal pathway. TMEPAI is ubiquitinated at its C-terminal region and ubiquitination modification of TMEPAI is a signal for its lysosomal trafficking. Moreover, TMEPAI binds the ubiquitin binding proteins Hrs and STAM which is required for its lysosomal transport. In addition, TMEPAI interacts with the dynactin pointed-end complex subunits dynactin 5 and dynactin 6. The aa 132–155 domain is essential for specific TMEPAI binding and deletion of this binding site leads to mis-trafficking of TMEPAI to the plasma membrane. These results reveal the pathway and mechanism regulating transport of TMEPAI to the lysosome, which helps to further understand the role of TMEPAI in tumorigenesis.