key: cord-0683787-k7s2hu2h
authors: D'Souza, Zinia; Taher, Farhana S.; Lupashin, Vladimir V.
title: Golgi inCOGnito: From vesicle tethering to human disease
date: 2020-07-27
journal: Biochim Biophys Acta Gen Subj
DOI: 10.1016/j.bbagen.2020.129694
sha: 4dc09789321a102a56bafa7306512426cdf35006
doc_id: 683787
cord_uid: k7s2hu2h

The Conserved Oligomeric Golgi (COG) complex, a multi-subunit vesicle tethering complex of the CATCHR (Complexes Associated with Tethering Containing Helical Rods) family, controls several aspects of cellular homeostasis by orchestrating retrograde vesicle traffic within the Golgi. The COG complex interacts with all key players regulating intra-Golgi trafficking, namely SNAREs, SNARE-interacting proteins, Rabs, coiled-coil tethers, and vesicular coats. In cells, COG deficiencies result in the accumulation of non-tethered COG-complex dependent (CCD) vesicles, dramatic morphological and functional abnormalities of the Golgi and endosomes, severe defects in N- and O- glycosylation, Golgi retrograde trafficking, sorting and protein secretion. In humans, COG mutations lead to severe multi-systemic diseases known as COG-Congenital Disorders of Glycosylation (COG-CDG). In this report, we review the current knowledge of the COG complex and analyze COG-related trafficking and glycosylation defects in COG-CDG patients.

glycosylation machinery is currently unknown and likely requires several novel adaptor proteins.

Apart from cytoplasmic sorting signals, length of the transmembrane domains (TMDs) of glycosylation enzymes might contribute to their retention and sorting within the Golgi. cis-Golgi resident proteins have shorter TMDs compared to late Golgi residents. Membrane thickness increases from ER to the PM due to the increasing concentration of sphingolipids and sterols. It is energetically favorable for shorter TMDs to be retained in thinner membranes and sorted into phospholipid-rich COPI vesicles rather than cholesterol-rich clathrin-coated vesicles targeted to the PM [16, 17] . Another proposed mechanism of Golgi enzyme retention is the formation of multimeric complexes. Sequentially acting glycosylation enzymes in the same cisternae can form dimers and higher-order oligomers. This increases the size of the protein preventing it from entering vesicles, leaving the Golgi. Oligomerization of sequentially acting enzymes also enhances the efficiency of glycosylation [18, 19] .

Also, the luminal environment within the Golgi governs glycosylation and Golgi homeostasis.

Each Golgi cisternae has a unique pH and ionic environment, which contributes to correct enzyme localization [20] and also regulates enzyme activity [21] . The contribution of these factors to Golgi homeostasis has been reviewed in Kellokumpu [22] . Furthermore, reduced luminal volume in flattened Golgi stacks facilitates enzymes-substrate encounters [23] .

Multi-subunit tethering complexes (MTCs) are a group of evolutionarily conserved vesicular tethers consisting of three to ten subunits. They are loosely sub-grouped into CATCHRs and non-CATCHRs [24] . CATCHR family includes MTCs functioning along the secretory pathway, namely, Dsl1/ZW10 complex, COG, GARP, EARP and the exocyst; non-CATCHR group includes CORVET and HOPS complexes which are involved in the endosomal trafficking.

TRAPP, a unique MTC in structure and function is involved in ER to Golgi trafficking and autophagy [25] . The subunits of Dsl1/ZW10, COG, GARP, and the exocyst complexes share similarities in their α-helical structures [26] . COG's closest relative is the exocyst, which is also octameric and the structure of its subunits SEC3/EXOC1, SEC5/EXOC2, SEC10/EXOC5, SEC15/EXOC6 and EXO70/EXOC7 are similar to COG subunits [27] [28] [29] . MTCs are peripheral membrane proteins that lack membrane anchoring domains and they can only associate with J o u r n a l P r e -p r o o f Journal Pre-proof membranes indirectly. So far, the GARP complex, Dsl1/ZW10 and the exocyst have been shown to be membrane associated via their interactions with Rab GTPases, SNAREs, and/or membrane lipids respectively [30] [31] [32] .

The COG complex has eight subunits ( Figure 2 ), encoded by eight different genes, and exists as a hetero-octameric complex or as lobe A (COG1, COG2, COG3, COG4) and lobe B subcomplexes (COG5, COG6, COG7, COG8) [33] . Interestingly, four subunits, COG3, COG4, COG6, and COG8, are more evolutionarily conserved, as are the other four subunits. COG1-COG8 interaction bridges the two subcomplexes together [34] [35] [36] . Mutations that disrupt COG1/8

interactions are detrimental for COG complex functions [37, 38] . The two subcomplexes are observed as lobes in deep-etch electron microscopy (EM) images of the purified COG complex from the bovine brain [39] . Lobe A predominantly associates with the Golgi membrane and can be found on every cisternae [40] , while lobe B preferentially interacts with vesicular membranes [38] . The observed cytoplasmic pool of COG is mainly octameric [29, 36, 38, 39] , while membrane-bound COG can be an octamer or a subcomplex [38] . COG subunits are possibly always bound to the membranes via weak protein-protein interactions with different peripheral or integral membrane proteins. Disruption of these interactions during cell lysis releases COG from the membranes and the soluble pool is likely to be an experimental artifact resulting from the cell lysis procedure. The different arrangements of the COG complex are tied to its functional state, which is described in the 'Current models for COG tethering' section. A slow recovery after photobleaching in Fluorescence Recovery After Photobleaching (FRAP) experiments show that the on/off cycling of COG subunits from the Golgi membrane is very slow [41] , and artificially membrane-glued COG is fully functional [42] .

Prolonged depletion or complete knockout of individual COG subunits causes morphological changes in the Golgi (severe fragmentation and dilation of all Golgi cisternae) ( Figure 3a ) that further alters glycosylation [48, 59] , and also affects the endolysosomal system (accumulation of Enlarged Endo-Lysosomal Structures, EELSs) [63] (Figure 3b ), delays retrograde protein trafficking [64] , causes protein missorting and changes the secretion profile [65] . Formation of intra-Golgi SNAREs complex STX5/GOSR1/BET1L/YKT6 [50] and trans-Golgi SNARE complex STX16/STX6/VTI1A/VAMP4 [66] is reduced in COG deficient cells. Another COGrelated trafficking abnormality is the delayed reaction to the fungal metabolite Brefeldin A (BFA) [60, 67] . BFA inhibits the exchange factor GBF1 for small GTPase Arf1, causing COPI coat dysfunction and an artificial fusion of Golgi and ER membranes [68] . The kinetics of both, BFA-induced Golgi "collapse" and subsequent Golgi restoration after BFA wash-out are severely delayed in COG deficient cells. This alteration is often interpreted as COG's requirement for Golgi-ER anterograde and retrograde trafficking [69, 70] . We believe that this interpretation is erroneous and that the altered response to BFA treatment is a secondary manifestation of GBF1, COPI, and/or SNARE malfunction in COG deficient cells [67] .

Importantly, many types of COG depleted mammalian cells have wild-type growth and division [48] , emphasizing that the COG complex is generally dispensable for intracellular anterograde trafficking.

The deletion of any of the COG subunits in human cells renders the entire complex nonfunctional and results in the degradation of several Golgi resident proteins. Proteins whose stability and function depend on the COG complex are termed COG sensitive proteins, or GEARS [71] . These include many Golgi glycosylation enzymes (MGAT1, MAN2A, B4GALT1, ST6GAL1) [60, 61] and certain members of the trafficking machinery (GS15/BET1L, GS28/GORS2, giantin/GOLGB1, golgin-84/GOLGA5) [71] . Importantly, not every Golgi protein is COG-sensitive; for instance, both the amount and localization of the SNARE STX5, CCT GM130/GOLGA2 and many of the Golgi Rabs are normal in COG-depleted cells [48, 71] (and our unpublished observations). This indicates the existence of COG-independent Golgi recycling/retention mechanism. Analysis of cell lines partially (siRNA) or completely (COG KOs) depleted for COG subunits laid a foundation for the analysis of COG complex deficiencies in humans, described in section 3.

J o u r n a l P r e -p r o o f

Another important evidence supporting the central role of the COG complex in cellular physiology comes from pathogen-host interaction research. Many intracellular pathogens hijack the host's membrane trafficking machinery to survive within them. Importantly, the COG complex is manipulated by viruses (SARS-Cov-2 [72] , Rift Valley fever [73] , HIV [74] , and

Orthopoxvirus [75] ), pathogenic bacteria (Chlamydia [76] and Brucella [77] ), and toxins (SubAB [48, 64] , Shiga [58] , and Cholera [48] ). It is not clear how these diverse groups of pathogens have evolved to rely on COG function.

The exact mechanism of COG complex function is still a mystery. Over the years, several models were put forward to explain various mutant phenotypes observed in COG-depleted cells (for review see [33] ). According to the most recent "assembly/disassembly" model [38] , lobe A The assembly/disassembly model would predict that the majority of Golgi associated octameric COG is inert. This then poses the question of what dissociates the two lobes to make them available for another round of vesicle tethering and fusion. While the exact mechanism of COG "recycling" is not understood, one possibility is that the specific binding to vesicular factors (coat, Rabs, SNAREs, CCTs) causes COG disassembly and association of lobe B with the vesicle membrane.

Since the past two decades, over a hundred individuals with COG mutations have been identified (see Figure 2 for the location of known mutations in COG subunits). As mentioned in the earlier section, the fidelity of glycosylation is largely dependent on the proper localization of the glycosylation machinery. So, it is not surprising that altered intra-Golgi trafficking due to COG malfunction leads to glycosylation defects [81] . [84] [85] [86] . COG mutations cause CDG-II. In COG-CDGs, the IEF pattern of serum transferrin indicates hyposialylated species, while IEF of apoC-III show increased non-glycosylated apoC-III and decreased monosialo glycoforms [81] .

Galactosylation and sialylation defects are also evident by mass-spectrometry in COG-CDGs.

Following diagnosis, genotyping is usually done to identify CDG-causing mutations. The next section summarizes the clinical findings of COG-CDG patients and tries to reconcile these findings with current knowledge on the COG complex's cellular functions. (p.L773R) in the COG4 gene [92] . The c.697G>T transcript underwent nonsense-mediated decay.

COG4 protein was depleted by 70%, but, curiously, no other subunits were significantly reduced.

Glycan mass-spectrometry showed protein sialylation and galactosylation defects. COG4 deficiency hampered COG's function and the Golgi failed to relocate to the ER upon BFA treatment. P2 carried a C>T point mutation at position 2185 in the COG4 gene resulting in R729W change. Though the child was born to unrelated parents -a father heterozygous for the aforementioned mutation and a normal mother, the child seemed to be homozygous for the C>T point mutation. This led the authors to speculate that the maternal allele, which was supposed to be normal, underwent deletion between intron 2 and exon 5. At the molecular level, only 20% of the COG4 protein is expressed. The deficiency of the COG4 subunit affected the stability of all the remaining lobe A subunits and COG5. Sequence and crystal structure analysis of COG4's Cterminal fragment by Richrdson et al [45] found that the mutated arginine is highly conserved. [112] .

The cellular phenotype and clinical presentations of COG-CDGs are heterogeneous, but the patients mainly exhibit neurological, morphological, skeletal, and hepatic abnormalities [94, 102, 114] (Figure 4) . One of the main reasons for heterogeneity could be because the mutations have varying effects on both stability and specific function of the mutant COG subunits (see Table 1 ) and the COG complex as a whole. Defects in Golgi glycosylation, particularly reduced sialylation and galactosylation, is the most common feature between COG-CDG patients and receptor binding and uptake [115] . Severe changes in copper homeostasis cause neurodegeneration and COG KO cells show altered stability and localization of copper transporters ATP7A and SLC31A1 [116] . Furthermore, altered glycosphingolipids synthesis in the COG-CDGs could be another possible explanation for neuronal involvement [117] . CDGs associated with the other lobe B subunit, COG5 [102] . Zeevaert et al [114] observed that COG8 deficiency mostly had neurological involvement, whereas growth retardation was a predominant feature in COG1 and COG7-CDG patients and dysmorphic features of face and hands are common in all CDG patients. Given the small cohort of COG-CDGs that have been reported, it is difficult to make further correlations between the affected subunit and clinical manifestations. Comparisons between the clinical phenotype of COG-CDGs should take into consideration the effect of the mutation on the affected COG subunit. In the recent retrospective analysis of COG-CDGs, Haijes et al [118] made such a comparison and concluded that lobe A mutations are more detrimental than lobe B mutation, but the discussion is not settled mainly because of the small number of known mutations and lack of robust data on these patients.

Treating congenital multi-systemic disorders is challenging and one single approach could be insufficient. A good example is the treatment of MPI-CDG. Clinical presentation of MPI-CDG includes but is not limited to liver fibrosis and gastrointestinal complications, thrombosis, and hypoglycemia. With oral mannose intake and liver transplantation, the patient improved dramatically [119] . Similarly, galactose supplementation has been used to alleviate some of the pathologies of PGM1-CDG [120] . Patients with mutations in TMEM165 have CDG-II and their J o u r n a l P r e -p r o o f Journal Pre-proof glycan profiles reveal hypogalactosylation. Two patients with TMEM165-CDG responded positively to galactose supplementation [121] . COG mutations cause a wide range of defects that directly (glycosylation enzymes, sugar transporters) and indirectly (Golgi homeostasis, cisternal compartmentalization, and stability of SNAREs and GEARs) impact glycosylation and other trafficking processes. Interestingly, data from our lab indicates that TMEM165 is dependent on the COG complex for its stability and its depletion in COG KO cells may contribute to misglycosylation (unpublished observations). If this prediction is correct, galactose therapy may partially alleviate hypoglycosylation in COG-CDGs. It is important to note that COG mutations not only affect the Golgi, but also the endolysosomal system, causing altered secretion and potential malfunction of the lysosomal degradation machinery [65] ; therefore, treatment of COG-CDG patients should combine strategies used for the treatment of both CDG and lysosomal disorders. Antisense therapy and gene therapy have not yet been well fully explored for the treatment of CDGs [122] . In TMEM165-CDG patient fibroblast, antisense therapy successfully rescued exon skipping due to an intronic mutation and drove expression of the WT protein [123] .

This approach is applicable where an intronic mutation leads to the activation of a cryptic splice site upstream of the canonical splice site. Antisense morpholino oligonucleotides block the cryptic splice site and promote canonical splicing. With the advancement in research on gene therapy, it could soon become a reality for the treatment of COG-CDGs. Theoretically, gene therapy should have promising outcomes in the treatment of COG-CDGs since the introduction of the WT copy of the affected COG subunit fully rescues COG-CDG defects in cell lines [63] .

At present, the significant challenges/risks include safe vehicular delivery and targeted integration of the delivered gene. Gene therapy, through intravenous and intramuscular liposomal delivery, rescued GNE-CDG (UDP-GlcNAc2 epimerase-CDG) in mice [124] . The establishment of a reliable animal COG disease model will benefit the development of therapeutics. There are some encouraging attempts to explore fly [125] and fish [91] Nevertheless, the molecular mechanism of COG-mediated vesicle tethering is only speculative and the exact molecular reactions and sequence of events leading to docking and fusion of retrograde membrane carriers at the Golgi are not fully understood. COG has multiple interactions with other components of a vesicle fusion machinery, but the temporal sequence of these protein-protein interactions is not clear. The prediction is that at least some COG interactions with the Golgi trafficking machinery are sequential rather than simultaneous since individual subunits interact with more than one trafficking partner. In vitro reconstitution of the COG complex function will undoubtedly help in answering this and other mechanistic questions.

So far, successful in vitro reconstitution was achieved only for one MTC, yeast HOPS complex [126] .

Which molecules are responsible for the COG complex's recruitment to the Golgi membrane?

CATCHRs employ diverse strategies for membrane association: Dsl1 is membrane-associated by ER anchored SNAREs [127] . The GARP complex is recruited by Arl5 [128] In yeast, the cytoplasm to vacuole targeting (Cvt) pathway is dependent on the activity of COG lobe A subunits. Autophagosome formation and the sorting of Atg proteins to the site of nucleation is affected in COG mutant cells [132] . This suggests that the COG complex might be involved in tethering events leading to autophagosome formation. Furthermore, one of the Atg proteins, Atg6 is dispersed in COG2 yeast mutants while several other Atg proteins have been shown to interact with COG subunits in yeast two-hybrid assays. At the TGN, COG8 controls

Atg9 trafficking in collaboration with Arl1 and Al3 GTPases [133] . If indeed COG is involved in autophagy, it would be worth studying the status of autophagy in COG-CDG patients and if found faulty, weigh in its impact on the COG-CDG phenotype.

The first COG subunits were discovered by the Monty Krieger lab 35 years ago [56] ; it took almost 20 years to realize that these proteins act together as an evolutionarily conserved vesicle tethering complex [29, 39] and that mutations in COG subunits are responsible for a whole family of human CDG-II diseases [105, 114] . We hope that the potent combination of molecular 

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