Institute of Molecular and Cellular Biology, National Taiwan University, No.1 Sec.4 Roosevelt Road, Taipei, 10617, Taiwan.
Development. 2013 Jul;140(13):2798-807. doi: 10.1242/dev.087171. Epub 2013 May 29.
The exostosin (EXT) genes encode glycosyltransferases required for glycosaminoglycan chain polymerization in the biosynthesis of heparan sulfate proteoglycans (HSPGs). Mutations in the tumor suppressor genes EXT1 and EXT2 disturb HSPG biosynthesis and cause multiple osteochondroma (MO). How EXT1 and EXT2 traffic within the Golgi complex is not clear. Here, we show that Rotini (Rti), the Drosophila GOLPH3, regulates the retrograde trafficking of EXTs. A reduction in Rti shifts the steady-state distribution of EXTs to the trans-Golgi. These accumulated EXTs tend to be degraded and their re-entrance towards the route for polymerizing GAG chains is disengaged. Conversely, EXTs are mislocalized towards the transitional endoplasmic reticulum/cis-Golgi when Rti is overexpressed. Both loss of function and overexpression of rti result in incomplete HSPGs and perturb Hedgehog signaling. Consistent with Drosophila, GOLPH3 modulates the dynamic retention and protein stability of EXT1/2 in mammalian species. Our data demonstrate that GOLPH3 modulates the activities of EXTs, thus implicating a putative role for GOLPH3 in the formation of MO.
外生蛋白（EXT）基因编码糖基转移酶，这些酶在肝素硫酸蛋白聚糖（HSPG）的生物合成中对于糖胺聚糖链聚合是必需的。肿瘤抑制基因 EXT1 和 EXT2 的突变扰乱了 HSPG 的生物合成，并导致多发性外生性骨软骨瘤（MO）。EXT1 和 EXT2 在高尔基体中的运输方式尚不清楚。在这里，我们表明果蝇 GOLPH3 的 Rotini（Rti）调节 EXT 的逆行运输。Rti 的减少将 EXT 的稳态分布转移到顺式高尔基体。这些积累的 EXT 往往会被降解，并且它们重新进入聚合 GAG 链的途径也会脱离。相反，当 Rti 过表达时，EXTs 会错误定位到过渡内质网/顺式高尔基体。rti 的功能丧失和过表达都会导致 HSPG 不完全，并扰乱 Hedgehog 信号通路。与果蝇一致，GOLPH3 调节哺乳动物物种中 EXT1/2 的动态保留和蛋白质稳定性。我们的数据表明，GOLPH3 调节 EXT 的活性，因此暗示 GOLPH3 在 MO 的形成中可能发挥作用。
