Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation
Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation
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DOI：
10.1091/mbc.e08-11-1136
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发表时间：
2009-05-01
影响因子：
3.3
通讯作者：
Polishchuk, Roman S.
中科院分区：
文献类型：
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作者：
Egorov, Mikhail V.;Capestrano, Mariagrazia;Polishchuk, Roman S.
FGD1 基因突变导致 X 连锁疾病，称为面生殖发育不良 (FGDY)。 FGD1 编码鸟嘌呤核苷酸交换因子，可特异性激活 GTPase Cdc42。反过来，Cdc42 是膜运输的重要调节因子，尽管人们对 FGD1 参与这一过程知之甚少。在发育过程中，FGD1 在骨骼生长和矿化过程中高度表达，因此功能蛋白的缺乏会导致严重的表型。蛋白质的分泌是骨形成所必需的过程，FGD1 的突变是否会改变蛋白质的分泌引起了人们的极大兴趣。我们最初在此表明 FGD1 优先与跨高尔基体网络 (TGN) 相关，表明它参与高尔基体蛋白质的输出。事实上，显性失活 FGD1 突变体的表达和 FGD1 的 RNA 干扰都会导致各种货物（包括成骨细胞中的骨特异性蛋白）的后高尔基体运输减少。活细胞成像显示，在 FGD1 缺陷细胞中，定向至细胞表面的高尔基体后转运中间体的形成受到抑制，这显然是由于 TGN 膜沿微管延伸的受损所致。这些作用取决于 FGD1 对 Cdc42 激活的调节及其与高尔基膜的关联，它们可能有助于 FGDY 发病机制。
Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). FGD1 encodes a guanine nucleotide exchange factor that specifically activates the GTPase Cdc42. In turn, Cdc42 is an important regulator of membrane trafficking, although little is known about FGD1 involvement in this process. During development, FGD1 is highly expressed during bone growth and mineralization, and therefore a lack of the functional protein leads to a severe phenotype. Whether the secretion of proteins, which is a process essential for bone formation, is altered by mutations in FGD1 is of great interest. We initially show here that FGD1 is preferentially associated with the trans-Golgi network (TGN), suggesting its involvement in export of proteins from the Golgi. Indeed, expression of a dominant-negative FGD1 mutant and RNA interference of FGD1 both resulted in a reduction in post-Golgi transport of various cargoes (including bone-specific proteins in osteoblasts). Live-cell imaging reveals that formation of post-Golgi transport intermediates directed to the cell surface is inhibited in FGD1-deficient cells, apparently due to an impairment of TGN membrane extension along microtubules. These effects depend on FGD1 regulation of Cdc42 activation and its association with the Golgi membranes, and they may contribute to FGDY pathogenesis.