School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin, 300457, China.
Sci Rep. 2017 Feb 20;7:42668. doi: 10.1038/srep42668.
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.
跨膜前列腺雄激素诱导蛋白（TMEPAI）已被报道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 向溶酶体的运输的分子机制尚不清楚。在这里，我们报告网格蛋白和 CI-M6PR 介导 TMEPAI 从高尔基体直接运输到内体-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 与泛素结合蛋白 Hrs 和 STAM 结合，这是其溶酶体运输所必需的。此外，TMEPAI 与动力蛋白正极复合物亚基动力蛋白 5 和动力蛋白 6 相互作用。aa132-155 结构域是 TMEPAI 特异性结合所必需的，并且该结合位点的缺失导致 TMEPAI 错误运输到质膜。这些结果揭示了调节 TMEPAI 向溶酶体运输的途径和机制，这有助于进一步了解 TMEPAI 在肿瘤发生中的作用。
