Rab40C is a novel Varp-binding protein that promotes proteasomal degradation of Varp in melanocytes.
Rab40C is a novel Varp-binding protein that promotes proteasomal degradation of Varp in melanocytes.
复制标题
DOI：
10.1242/bio.201411114
复制
发表时间：
2015-02-06
期刊：
影响因子：
2.4
通讯作者：
Fukuda M
中科院分区：
文献类型：
--
作者：
Yatsu A;Shimada H;Ohbayashi N;Fukuda M
Varp（VPS9-锚蛋白重复蛋白）最初通过其 VPS9 结构域被鉴定为小 GTP 酶 Rab21 的激活剂，但随后被证明通过其第一个 ANKR1 结构域发挥 Rab32/38 效应子的作用。尽管 Varp 的这些功能对于黑素生成很重要，但 Varp 包含第二个 ANKR2 结构域，其功能仍然完全未知。在这里，我们鉴定了 Rab40C（一种包含 SOCS 盒的非典型 Rab，可招募泛素连接酶复合物）作为一种新型 ANKR2 结合蛋白，并研究了其在黑素细胞中黑素生成酶运输中的参与。结果表明，黑素细胞中 Rab40C 的过表达通过 SOCS-box 依赖性方式促进 Varp 的蛋白酶体降解，导致黑色素生成酶 Tyrp1 信号急剧减少，并且黑素细胞中 Rab40C 的敲低导致 Varp 量增加。有趣的是，Rab40C 敲低也导致 Tyrp1 信号急剧减少，与 Varp 过度表达相同。这些发现表明，Rab40C 通过控制 Varp 的蛋白酶体降解，成为之前意想不到的黑色素细胞中 Tyrp1 运输的调节剂。
Varp (VPS9-ankyrin repeat protein) was originally identified as an activator of small GTPase Rab21 through its VPS9 domain, but it has subsequently been shown to function as a Rab32/38 effector through its first ANKR1 domain. Although these functions of Varp are important for melanogenesis, Varp contains a second ANKR2 domain, whose function remained completely unknown. Here we identified Rab40C, an atypical Rab containing a SOCS box that recruits a ubiquitin ligase complex, as a novel ANKR2-binding protein and investigated its involvement in melanogenic enzyme trafficking in melanocytes. The results showed that overexpression of Rab40C in melanocytes caused a dramatic reduction in melanogenic enzyme Tyrp1 signals by promoting proteasomal degradation of Varp in a SOCS-box-dependent manner and that knockdown of Rab40C in melanocytes caused an increase in the amount of Varp. Intriguingly, Rab40C knockdown also caused a dramatic reduction in Tyrp1 signals, the same as Varp overexpression did. These findings indicated that Rab40C is a previously unexpected regulator of Tyrp1 trafficking in melanocytes through controlling the proteasomal degradation of Varp.
登录
查看更多内容
影响因子：
11.8
作者：
Hesketh, Geoffrey G.;Perez-Dorado, Inmaculada;Jackson, Lauren R.;Wartosch, Lena;Schaefer, Ingmar B.;Gray, Sally R.;McCoy, Airlie J.;Zeldin, Oliver B.;Garman, Elspeth F.;Harbour, Michael E.;Evans, Philip R.;Seaman, Matthew N. J.;Luzio, J. Paul;Owen, David J.
通讯作者：
Owen, David J.
影响因子：
9.2
作者：
Gerondopoulos, Andreas;Langemeyer, Lars;Liang, Jin-Rui;Linford, Andrea;Barr, Francis A.
通讯作者：
Barr, Francis A.
影响因子：
4.8
作者：
Fukuda, M;Kanno, E;Mikoshiba, K
通讯作者：
Mikoshiba, K
影响因子：
30.8
作者：
Ménasché, G;Pastural, E;de Saint Basile, G
通讯作者：
de Saint Basile, G
影响因子：
7.5
作者：
Marks, Michael S.;Heijnen, Harry F. G.;Raposo, Graca
通讯作者：
Raposo, Graca