Distinct functions of human MVB12A and MVB12B in the ESCRT-I dependent on their posttranslational modifications.
Distinct functions of human MVB12A and MVB12B in the ESCRT-I dependent on their posttranslational modifications.
复制标题
DOI：
10.1016/j.bbrc.2010.07.060
复制
发表时间：
2010-08
影响因子：
3.1
通讯作者：
Takumi Tsunematsu;E. Yamauchi;H. Shibata;M. Maki;T. Ohta;H. Konishi
中科院分区：
文献类型：
--
作者：
Takumi Tsunematsu;E. Yamauchi;H. Shibata;M. Maki;T. Ohta;H. Konishi
ESCRT-I 介导泛素化货物蛋白从质膜到内体囊泡的分选，包含 TSG101 (Vps23)、Vps28、Vps37 和 MVB12 蛋白的异四聚体。在人类中，结构相似的亚型 MVB12A 和 MVB12B 是 ESCRT-I 的亚基。然而，尚未描述这些蛋白质的功能描述。在这里，我们展示了两种 MVB12 蛋白的酪氨酸磷酸化和泛素化对其各自功能的不同影响。正如我们之前的研究中所指出的，MVB12A 响应表皮生长因子 (EGF) 刺激而发生的 Tyr204 磷酸化会影响与 CD2AP 的结合，从而调节与 ESCRT-I 结合的 EGF 受体的量。引人注目的是，MVB12B 的 Lys264 和 Lys290 泛素化被诱导，导致 MVB12B 在 COS-7 细胞中不稳定并包含在内。这些泛素化在 EGF 刺激下增加，这是由 MVB12B 的 Tyr241 和 Tyr243 磷酸化调节的。此外，MVB12A 还参与了 MVB12B 的易聚集蛋白。这些结果表明，MVB12B 的表达通常可能通过泛素-蛋白酶体途径受到抑制，该途径同时调节 MVB12A 的命运和 ESCRT-I 的功能。
ESCRT-I, which mediates the sorting of ubiquitinated cargo protein from the plasma membrane to the endosomal vesicle, comprises a heterotetramer of TSG101 (Vps23), Vps28, Vps37 and MVB12 protein. In humans, the structurally similar subtypes MVB12A and MVB12B are subunits of ESCRT-I. However, no functional description of these proteins has been described. Here we show the differing effects of tyrosine phosphorylation and ubiquitination of both MVB12 proteins on their respective functions. As noted in our previous study, Tyr204 phosphorylation of MVB12A in response to epidermal growth factor (EGF) stimulation affects binding to CD2AP, which regulates the amounts of EGF receptor bound to ESCRT-I. Strikingly, ubiquitination of Lys264 and Lys290 of MVB12B was induced and led to the instability and inclusion of MVB12B in COS-7 cells. These ubiquitinations increased upon EGF stimulation, which was regulated by the phosphorylations of Tyr241 and Tyr243 of MVB12B. Furthermore, MVB12A was also involved in the aggregation-prone proteins of MVB12B. These results suggest that the expression of MVB12B may be normally suppressed through the ubiquitin–proteasome pathway that simultaneously regulates the fate of MVB12A and the functions of ESCRT-I.