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

Witkos, Tomasz M.; Chan, Wing Lee; Joensuu, Merja; Rhiel, Manuel; Pallister, Edward; Thomas‐Oates, Jane; Mould, A. Paul; Mironov, Aleksandr; Biot, Christophe; Guérardel, Yann; Morelle, Willy; Ungár, Dániel; Wieland, Felix; Jokitalo, Eija; Tassabehji, May; Kornak, Uwe; Lowe, Martin

doi:10.1038/s41467-018-08044-6

Cited by 43 publications

(76 citation statements)

References 75 publications

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“…GORAB promotes COPI recruitment to the trans-Golgi through the formation of stable membrane domains. GORAB also scaffolds the catalytically inactive protein kinase Scyl1 [125]. Scyl1 localizes to the ERGIC and cis-Golgi budding sites and binds to COPI coats using a C-terminal RKLD sequence, similar to the KKXX COPI-binding motif present in ER transmembrane proteins.…”

Section: Golgins Grasps Gorab and Rabsmentioning

confidence: 99%

Sugary Logistics Gone Wrong: Membrane Trafficking and Congenital Disorders of Glycosylation

Linders

Peters

Beest

et al. 2020

IJMS

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Glycosylation is an important post-translational modification for both intracellular and secreted proteins. For glycosylation to occur, cargo must be transported after synthesis through the different compartments of the Golgi apparatus where distinct monosaccharides are sequentially bound and trimmed, resulting in increasingly complex branched glycan structures. Of utmost importance for this process is the intraorganellar environment of the Golgi. Each Golgi compartment has a distinct pH, which is maintained by the vacuolar H+-ATPase (V-ATPase). Moreover, tethering factors such as Golgins and the conserved oligomeric Golgi (COG) complex, in concert with coatomer (COPI) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion, efficiently deliver glycosylation enzymes to the right Golgi compartment. Together, these factors maintain intra-Golgi trafficking of proteins involved in glycosylation and thereby enable proper glycosylation. However, pathogenic mutations in these factors can cause defective glycosylation and lead to diseases with a wide variety of symptoms such as liver dysfunction and skin and bone disorders. Collectively, this group of disorders is known as congenital disorders of glycosylation (CDG). Recent technological advances have enabled the robust identification of novel CDGs related to membrane trafficking components. In this review, we highlight differences and similarities between membrane trafficking-related CDGs.

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Section: Golgins Grasps Gorab and Rabsmentioning

confidence: 99%

Sugary Logistics Gone Wrong: Membrane Trafficking and Congenital Disorders of Glycosylation

Linders

Peters

Beest

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…COPI subunits are essential for notochord development in zebrafish (19). In humans, geroderma osteodysplasticum is caused by loss of the COPI scaffold protein GORAB (20), and defects in ARCN1, encoding COPI complex subunit, are associated with syndromic rhizomelic short stature (21).…”

Section: Introductionmentioning

confidence: 99%

COPB2haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

Marom¹,

Burrage²,

Clément³

et al. 2020

Preprint

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Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures and developmental delay of variable severity. Because the role of COPB2 in bone has not been characterized, we studied the effect of COPB2 deficiency on skeletal development in mice and zebrafish. Copb2+/− mice showed low bone mass and decreased bone strength. In zebrafish, larvae carrying a copb2 heterozygous frameshift variant showed delayed mineralization. copb2-null embryos showed endoplasmic reticulum (ER) and Golgi disorganization, and embryonic lethality. COPB2 siRNA-treated fibroblasts showed delayed collagen trafficking with retention of type I collagen in the ER and Golgi, and altered distribution of Golgi markers. Our data suggest that COPB2 haploinsufficiency leads to disruption of intracellular collagen trafficking and osteoporosis, which may improve with ascorbic acid supplementation. This work highlights the role of COPI complex as a critical regulator of bone mass and identifies a new form of coatopathy due to COPB2 deficiency.

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“…GORAB, the protein mutated in this disease, has been localized to the trans-Golgi and is involved in COPI trafficking. COPI is required for recycling of Golgi resident proteins; thus loss of GORAB function results in reduced recycling of trans-Golgi enzymes as demonstrated by mislocalization of sialyltransferase and improper Nglycosylation of cargo proteins [122]. It is likely that trans-Golgi enzymes involved in the modification and processing of O-linked glycan chains, such as GAGs, are also affected.…”

Section: Disorders Linked To Proteins Involved In the Synthesis Of Thmentioning

confidence: 99%

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

et al. 2019

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Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides that constitute the carbohydrate moiety covalently attached to the protein core of proteoglycans, macromolecules present on the cell surface and in the extracellular matrix. Several genetic disorders of bone and connective tissue are caused by mutations in genes encoding for glycosyltransferases, sulfotransferases and transporters that are responsible for the synthesis of sulfated GAGs. Phenotypically, these disorders all reflect alterations in crucial biological functions of GAGs in the development, growth and homoeostasis of cartilage and bone. To date, up to 27 different skeletal phenotypes have been linked to mutations in 23 genes encoding for proteins involved in GAG biosynthesis. This review focuses on recent genetic, molecular and biochemical studies of bone and connective tissue disorders caused by GAG synthesis defects. These insights and future research in the field will provide a deeper understanding of the molecular pathogenesis of these disorders and will pave the way for developing common therapeutic strategies that might be targeted to a range of individual phenotypes.

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

Cited by 43 publications

References 75 publications

Sugary Logistics Gone Wrong: Membrane Trafficking and Congenital Disorders of Glycosylation

Sugary Logistics Gone Wrong: Membrane Trafficking and Congenital Disorders of Glycosylation

COPB2haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

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