The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin-proteasome pathway and macroautophagy.
The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin-proteasome pathway and macroautophagy.
复制标题
泛素连接酶F-box/G-蛋白蛋白1通过泛素蛋白 - 蛋白酶体途径和大型噬菌体促进疾病连接的蛋白torsina的降解。
DOI：
10.1016/j.neuroscience.2012.08.023
复制
发表时间：
2012-11-08
期刊：
影响因子：
3.3
通讯作者：
Gonzalez-Alegre, P.
中科院分区：
文献类型：
--
作者：
Gordon, K. L.;Glenn, K. A.;Bode, N.;Wen, H. M.;Paulson, H. L.;Gonzalez-Alegre, P.
DYT 1肌张力障碍是一种显性遗传的致残性神经系统疾病，由蛋白质torsinA中的谷氨酸（ΔE）缺失引起。我们先前表明，torsinA（wt）通过大自噬降解，而torsinA（ΔE）靶向泛素蛋白酶体途径（UPP）。torsinA（wt）和（ΔE）的不同催化剂可能调节torsinA（wt）：torsinA（ΔE）的化学计量。因此，从机制上了解蛋白质质量控制机制如何清除神经元中的扭转蛋白A（ΔE）可能会揭示疾病发病机制中的重要调节步骤。在这里，我们想知道FBG 1（一种已知降解神经元糖蛋白的泛素连接酶）是否与UPP降解torsinA（ΔE）有关。在培养细胞中完成的第一组研究中，我们表明FBG 1与扭转蛋白A（wt）和（ΔE）的稳态水平相互作用并影响其水平。有趣的是，FBG 1不仅通过UPP，而且通过巨自噬来促进torsinA的降解。为了确定这些发现的潜在临床意义，我们询问了消除Fbg 1表达是否会触发小鼠中torsinA（ΔE）敲除的运动表型，这是一种非表现性DYT 1突变携带者模型。我们检测到老年torsinA（ΔE）敲入-Fbg 1敲除小鼠和对照小鼠之间自发运动的差异。此外，神经元水平的torsinA在Fbg 1 null小鼠中没有改变，表明冗余系统可能在体内补偿这种泛素连接酶的缺乏。总之，我们的研究支持FBG 1对torsinA降解的非必要作用，并揭示了FBG 1与自噬途径的新联系。
DYT1 dystonia is a dominantly inherited, disabling neurological disorder with low penetrance that is caused by the deletion of a glutamic acid (ΔE) in the protein torsinA. We previously showed that torsinA(wt) is degraded through macroautophagy while torsinA(ΔE) is targeted to the ubiquitin proteasome pathway (UPP). The different catabolism of torsinA(wt) and (ΔE) potentially modulates torsinA(wt):torsinA(ΔE) stoichiometry. Therefore, gaining a mechanistic understanding on how the protein quality control machinery clears torsinA(ΔE) in neurons may uncover important regulatory steps in disease pathogenesis. Here, we asked whether FBG1, a ubiquitin ligase known to degrade neuronal glycoproteins, is implicated in the degradation of torsinA(ΔE) by the UPP. In a first set of studies completed in cultured cells, we show that FBG1 interacts with and influences the steady-state levels of torsinA(wt) and (ΔE). Interestingly, FBG1 achieves this effect promoting the degradation of torsinA not only through the UPP, but also by macroautophagy. To determine the potential clinical significance of these findings, we asked if eliminating expression of Fbg1 triggers a motor phenotype in torsinA(ΔE) knock in mice, a model of non-manifesting DYT1 mutation carriers. We detected differences in spontaneous locomotion between aged torsinA(ΔE) knock in-Fbg1 knock out and control mice. Furthermore, neuronal levels of torsinA were unaltered in Fbg1 null mice, indicating that redundant systems likely compensate in vivo for the absence of this ubiquitin ligase. In summary, our studies support a non-essential role for FBG1 on the degradation of torsinA and uncover a novel link of FBG1 to the autophagy pathway.
登录
查看更多内容
影响因子：
7.8
作者：
Gong B;Chen F;Pan Y;Arrieta-Cruz I;Yoshida Y;Haroutunian V;Pasinetti GM
通讯作者：
Pasinetti GM
DOI：
10.1073/pnas.0701185104
发表时间：
2007-04-24
影响因子：
11.1
作者：
Hewett, Jeffrey W.;Tannous, Bakhos;Breakefield, Xandra O.
通讯作者：
Breakefield, Xandra O.
DOI：
10.1073/pnas.0304375101
发表时间：
2004-01-20
影响因子：
11.1
作者：
Goodchild, RE;Dauer, WT
通讯作者：
Dauer, WT
影响因子：
3.5
作者：
Hewett, J;Gonzalez-Agosti, C;Breakefield, XO
通讯作者：
Breakefield, XO
影响因子：
6.1
作者：
Grundmann, K.;Reischmann, B.;Riess, O.
通讯作者：
Riess, O.