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GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

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Author(s)

  • Tomasz M. Witkos
  • Wing Lee Chan
  • Merja Joensuu
  • Manuel Rhiel
  • Ed Pallister
  • Jane Elizabeth Thomas-Oates
  • Paul Mould
  • Alex A. Mironov
  • Christophe Biot
  • Yann Guerardel
  • Willy Morelle
  • Daniel Ungar
  • Felix T. Wieland
  • Eija Jokitalo
  • May Tassabehji
  • Uwe Kornak
  • Martin Lowe

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Publication details

JournalNature Communications
DateAccepted/In press - 6 Dec 2018
DatePublished (current) - 10 Jan 2019
Original languageEnglish

Abstract

COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI- mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is major disease mechanism in gerodermia osteodysplastica.

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