The Drosophila GOLPH3 homolog regulates the biosynthesis of heparan sulfate proteoglycans by modulating the retrograde trafficking of exostosins

Wei Ling Chang, Che Wei Chang, Yu Yun Chang, Hsin Ho Sung, Ming Der Lin, Shu Chuan Chang, Chung Hao Chen, Chia Wei Huang, Kuei Shu Tung, Tze Bin Chou

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2798-2807
Number of pages10
JournalDevelopment (Cambridge)
Volume140
Issue number13
DOIs
Publication statusPublished - 2013

Keywords

  • EXT
  • GOLPH3
  • HSPGs

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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