A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1–Cog8 interaction in COG complex formation

Foulquier, François; Ungár, Dániel; Reynders, Ellen; Zeevaert, Renate; Mills, Philippa; García‐Silva, María Teresa; Briones, Paz; Winchester, Bryan; Morelle, Willy; Krieger, Monty; Annaert, Willem; Matthijs, Gert

doi:10.1093/hmg/ddl476

Cited by 111 publications

(123 citation statements)

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“…Mutations in the genes encoding human COG1, COG4-COG8 have been associated with congenital disorders of glycosylation (CDG) (Foulquier et al, 2006;Foulquier et al, 2007;Kranz et al, 2007;Lübbehusen et al, 2010;Ng et al, 2007;Paesold-Burda et al, 2009;Reynders et al, 2009;Spaapen et al, 2005;Steet and Kornfeld, 2006;Wu et al, 2004) suggesting a role for COG in the retention and/or retrieval of Golgi glycosylation enzymes. Indeed, loss of COG subunits impaired the localisation and the stability of Golgi resident proteins, which are known to recycle within the Golgi stacks (Oka et al, 2004;Zolov and Lupashin, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In yeast, subunits of Lobe A are essential components of the complex (VanRheenen et al, 1998;Whyte and Munro, 2001;Wuestehube et al, 1996), whereas Lobe B subunits are not substantially required for cell growth or internal membrane organisation (Ram et al, 2002;Whyte and Munro, 2001). Mutations in the genes encoding human COG1, COG4-COG8 have been associated with congenital disorders of glycosylation (CDG) (Foulquier et al, 2006Foulquier et al, 2007Kranz et al, 2007;Lübbehusen et al, 2010;Ng et al, 2007;Paesold-Burda et al, 2009;Reynders et al, 2009;Spaapen et al, 2005;Steet and Kornfeld, 2006;Wu et al, 2004) indicating a role for COG in the transport and/or stability of Golgi glycosylation enzymes. Indeed studies in both yeast and mammalian cells have suggested that COG complex might function as a vesicle-tethering factor in intra-Golgi retrograde COPI transport (Ungar et al, 2002), thus regulating the distribution and the stability of Golgi resident proteins (Oka et al, 2004;Shestakova et al, 2006;Suvorova et al, 2001;Suvorova et al, 2002;Walter et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Mutations inCog7affect Golgi structure, meiotic cytokinesis and sperm development duringDrosophilaspermatogenesis

Belloni

Sechi

Riparbelli

et al. 2012

Journal of Cell Science

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SummaryThe conserved oligomeric Golgi (COG) complex plays essential roles in Golgi function, vesicle trafficking and glycosylation. Deletions in the human COG7 gene are associated with a rare multisystemic congenital disorder of glycosylation that causes mortality within the first year of life. In this paper, we characterise the Drosophila orthologue of COG7 (Cog7). Loss-of-function Cog7 mutants are viable but male sterile. The Cog7 gene product is enriched in the Golgi stacks and in Golgi-derived structures throughout spermatogenesis. Mutations in the Cog7 gene disrupt Golgi architecture and reduce the number of Golgi stacks in primary spermatocytes. During spermiogenesis, loss of the Cog7 protein impairs the assembly of the Golgi-derived acroblast in spermatids and affects axoneme architecture. Similar to the Cog5 homologue, four way stop (Fws), Cog7 enables furrow ingression during cytokinesis. We show that the recruitment of the small GTPase Rab11 and the phosphatidylinositol transfer protein Giotto (Gio) to the cleavage site requires a functioning wild-type Cog7 gene. In addition, Gio coimmunoprecipitates with Cog7 and with Rab11 in the testes. Our results altogether implicate Cog7 as an upstream component in a gio-Rab11 pathway controlling membrane addition during cytokinesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutations inCog7affect Golgi structure, meiotic cytokinesis and sperm development duringDrosophilaspermatogenesis

Belloni

Sechi

Riparbelli

et al. 2012

Journal of Cell Science

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“…Among the known multisubunit tethering complexes, only COG (23)(24)(25)(26)(27)(28) and TRAPP (29) have been directly implicated in human genetic disease. Mutations in the Cog1 (24), Cog7 (26)(27)(28), and Cog8 (23,25) subunits cause type II congenital disorders of glycosylation (CDGs).…”

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confidence: 99%

Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene

Richardson

Smith

Ungár

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The proper glycosylation of proteins trafficking through the Golgi apparatus depends upon the conserved oligomeric Golgi (COG) complex. Defects in COG can cause fatal congenital disorders of glycosylation (CDGs) in humans. The recent discovery of a form of CDG, caused in part by a COG4 missense mutation changing Arg 729 to Trp, prompted us to determine the 1.9 Å crystal structure of a Cog4 C-terminal fragment. Arg 729 is found to occupy a key position at the center of a salt bridge network, thereby stabilizing Cog4's small C-terminal domain. Studies in HeLa cells reveal that this C-terminal domain, while not needed for the incorporation of Cog4 into COG complexes, is essential for the proper glycosylation of cell surface proteins. We also find that Cog4 bears a strong structural resemblance to exocyst and Dsl1p complex subunits. These complexes and others have been proposed to function by mediating the initial tethering between transport vesicles and their membrane targets; the emerging structural similarities provide strong evidence of a common evolutionary origin and may reflect shared mechanisms of action.congenital disorder of glycosylation ͉ Golgi apparatus ͉ multi-subunit tethering complex ͉ vesicle trafficking ͉ X-ray crystallography M ultiple lines of evidence implicate the conserved oligomeric Golgi (COG) complex in retrograde transport within the Golgi apparatus (1, 2). For example, partial knockdown of mammalian COG3 permitted exocytosis, while simultaneously blocking the retrograde transport of Shiga toxin from endosomes to the ER (3). COG was initially isolated from bovine brain on the basis of its ability to stimulate an in vitro Golgi transport assay (4). Two of its 8 subunits, Cog1/ldlB and Cog2/ ldlC, had previously been identified in a genetic screen for compromised cell surface receptor stability (5, 6). In the yeast Saccharomyces cerevisiae, the COG complex was discovered through studies of one of its subunits, Cog8p/Dor1p. Implicated in vesicle targeting to the Golgi apparatus, Cog8p was found to co-immunoprecipitate with 7 other polypeptides (7). The 7 associated polypeptides included two (Cog2p/Sec35p and Cog3p/ Sec34p) that had earlier been identified in genetic screens for temperature-sensitive mutations causing secretion defects (8). In further support of a role in trafficking to and within the Golgi, COG interacts physically with a large number of Golgi-localized trafficking factors, including (in yeast) the Rab family G protein Ypt1p, the SNAREs Sed5p, Ykt6p, Gos1p, and Sec22p, and COPI vesicle coat proteins (9).COG is one of several large protein complexes proposed to function as multisubunit tethering factors, mediating the initial interaction between transport vesicles and their target membranes (2, 10-12). For many of these complexes, a dearth of structural information has slowed the development of mechanistic models and has made it difficult to know how-or whether-to apply lessons learned from studies of one complex to another. Subunits of the COG, exocyst, Dsl1p, and Golgiassoci...

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“…The most severe diseases are observed for COG6, COG7 and COG8 mutations, associated with severe neurological impairment, liver dysfunction, and infantile lethality [52][53][54][55]. The identification of milder cases of COG6 and COG7 deficiency harboring different mutations [56,57] however shows that the severity of the disease does not simply relate to the subunit affected but rather to the capability of forming a fully functional COG complex.…”

Section: Localization Of Glycosyltransferasesmentioning

confidence: 99%

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

Hennet

Cabalzar

2015

Trends in Biochemical Sciences

112

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Glycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways not only revealed tremendous diversity in functional impairments, but also pointed to phenotypic similarities, emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview of the significance of glycosylation in human development and physiology. Congenital disorders of glycosylation -a consice chart of glycocalyx dysfunctionThierry Hennet, Jürg Cabalzar Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland AbstractGlycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways has revealed a tremendous diversity of functional impairments bus also pointed to phenotypic similarities emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview on the significance of glycosylation in human development and physiology. Highlights Congenital disorders underline the role of glycosylation in human development.  Next-gen sequencing techniques expanded the discovery of glycosylation gene defects.  The clinical variability of glycosylation disorders implies they are underdiagnosed. Glycosylation disordersGlycosylation is by far the most complex form of protein [1,2] and lipid modification [3,4] in all domains of life. The tremendous diversity of glycoconjugate structures resulting from intricate biosynthetic pathways is a major factor hampering the assignment of functions to glycans chains. Much has been learnt from the study of disrupted glycosylation genes in model organisms, thereby establishing numerous essential contributions of glycans in regulating cell and organ functions [5]. The study of human diseases of glycosylation brings additional insights by providing a more differentiated view on glycan functions. Indeed, most human mutations are hypomorphic, thus causing partial loss of glycosylation reactions that lead to variable clinical manifestations.Diseases of glycosylation are also referred to as congenital disorders of glycosylation (CDG). Given the heterogeneity of glycans, the clinical scope of CDG is considerable, ranging from nearly normal phenotypes to sever...

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A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1–Cog8 interaction in COG complex formation

Cited by 111 publications

References 24 publications

Mutations inCog7affect Golgi structure, meiotic cytokinesis and sperm development duringDrosophilaspermatogenesis

Mutations inCog7affect Golgi structure, meiotic cytokinesis and sperm development duringDrosophilaspermatogenesis

Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

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