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

TY - JOUR

T1 - GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

AU - Witkos, Tomasz M.

AU - Chan, Wing Lee

AU - Joensuu, Merja

AU - Rhiel, Manuel

AU - Pallister, Ed

AU - Thomas-Oates, Jane Elizabeth

AU - Mould, Paul

AU - Mironov, Alex A.

AU - Biot, Christophe

AU - Guerardel, Yann

AU - Morelle, Willy

AU - Ungar, Daniel

AU - Wieland, Felix T.

AU - Jokitalo, Eija

AU - Tassabehji, May

AU - Kornak, Uwe

AU - Lowe, Martin

PY - 2019/1/10

Y1 - 2019/1/10

N2 - 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.

AB - 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.

KW - Bone Diseases/congenital

KW - Carrier Proteins/genetics

KW - Cells, Cultured

KW - Coat Protein Complex I/genetics

KW - Dwarfism/genetics

KW - Enzymes/metabolism

KW - Glycosylation

KW - Golgi Apparatus/metabolism

KW - HEK293 Cells

KW - HeLa Cells

KW - Humans

KW - Mutation

KW - Protein Binding

KW - Protein Transport

KW - RNA Interference

KW - Skin Diseases, Genetic/genetics

KW - Transcription Factors/genetics

UR - http://www.scopus.com/inward/record.url?scp=85059828124&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-08044-6

DO - 10.1038/s41467-018-08044-6

M3 - Article

C2 - 30631079

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 127

ER -