Golgi membrane protein Erd1 Is essential for recycling a subset of Golgi glycosyltransferases

Sardana, Richa; CMH, Highland; Straight, Beth E; Chavez, Christopher F; Fromme, J. Christopher; Emr, Scott D.

doi:10.7554/elife.70774

Cited by 9 publications

(8 citation statements)

References 62 publications

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“…The most prominent GARP-dependent displacement was observed for the COPI adaptor protein GOLPH3. GOLPH3 plays a crucial role in sorting a subset of Golgi resident glycosyltransferases back to Golgi by binding to the cytoplasmic tails of Golgi glycosyltransferases to package them into recycling COPI vesicles ( Schmitz et al, 2008 ; Tu et al, 2008 ; Frappaolo et al, 2020 ; Lowe, 2021 ; Sardana et al, 2021 ; Welch et al, 2021 ), and its displacement from the Golgi in GARP deficient cells could be responsible for some glycosylation defects in mutant cells. Displacement of GOLPH3, however, could not explain the depletion of B4GALT1 and MGAT1 in GARP-KO cells ( Khakurel et al, 2021 ), since GOLPH3 is not responsible for their Golgi retention.…”

Section: Discussionmentioning

confidence: 99%

GARP dysfunction results in COPI displacement, depletion of Golgi v-SNAREs and calcium homeostasis proteins

Khakurel

Kudlyk

Pokrovskaya

et al. 2022

Front. Cell Dev. Biol.

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Golgi-associated retrograde protein (GARP) is an evolutionary conserved heterotetrameric protein complex that tethers endosome-derived vesicles and is vital for Golgi glycosylation. Microscopy and proteomic approaches were employed to investigate defects in Golgi physiology in RPE1 cells depleted for the GARP complex. Both cis and trans-Golgi compartments were significantly enlarged in GARP-knock-out (KO) cells. Proteomic analysis of Golgi-enriched membranes revealed significant depletion of a subset of Golgi residents, including Ca2+ binding proteins, enzymes, and SNAREs. Validation of proteomics studies revealed that SDF4 and ATP2C1, related to Golgi calcium homeostasis, as well as intra-Golgi v-SNAREs GOSR1 and BET1L, were significantly depleted in GARP-KO cells. Finding that GARP-KO is more deleterious to Golgi physiology than deletion of GARP-sensitive v-SNAREs, prompted a detailed investigation of COPI trafficking machinery. We discovered that in GARP-KO cells COPI is significantly displaced from the Golgi and partially relocalized to the ER-Golgi intermediate compartment (ERGIC). Moreover, COPI accessory proteins GOLPH3, ARFGAP1, GBF1, and BIG1 are also relocated to off-Golgi compartments. We propose that the dysregulation of COPI machinery, along with the depletion of Golgi v-SNAREs and alteration of Golgi Ca2+ homeostasis, are the major driving factors for the depletion of Golgi resident proteins, structural alterations, and glycosylation defects in GARP deficient cells.

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Section: Discussionmentioning

confidence: 99%

GARP dysfunction results in COPI displacement, depletion of Golgi v-SNAREs and calcium homeostasis proteins

Khakurel

Kudlyk

Pokrovskaya

et al. 2022

Front. Cell Dev. Biol.

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“…Two COPI associated proteins, GOLPH3 and ARFGAP1 are also displaced from the Golgi in GARP-KO cells, not to the ERGIC, but likely dissociate to cytoplasm. GOLPH3 plays a crucial role in sorting of a subset of Golgi resident glycosyltransferases back to Golgi by binding to the cytoplasmic tails of Golgi glycosyltransferases to package them into recycling COPI vesicles [46,47,[70][71][72][73], and its displacement from the Golgi in GARP deficient cells could be responsible for some glycosylation defects in mutant cells. Displacement of GOLPH3, however, could not explain the instability of B4GALT1 and MGAT1 in GARP-KO cells [42], since GOLPH3 is not responsible for their Golgi retention.…”

Section: Discussionmentioning

confidence: 99%

GARP complex controls Golgi physiology by stabilizing COPI machinery and Golgi v-SNAREs

Khakurel

Kudlyk

Pokrovskaya

et al. 2022

Preprint

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GARP is an evolutionary conserved heterotetrameric protein complex that is thought to tether endosome-derived vesicles and promotes their fusion in the trans-Golgi network. We have previously discovered the GARP's role in maintaining Golgi glycosylation machinery. To further investigate the importance of the GARP complex for Golgi physiology, we employed Airyscan superresolution and electron microscopy, as well as the unbiased quantitative proteomic analysis of Golgi in RPE1 cells. Both cis and trans-Golgi compartments were significantly enlarged in GARP deficient cells with pronounced alterations of TGN morphology. In GARP-KO cells, proteomic analysis revealed a depletion of a subset of Golgi resident proteins, including Ca2+ binding proteins, glycosylation enzymes, and v-SNAREs. We validated proteomics studies and discovered that two Golgi-resident proteins SDF4 and ATP2C1, related to Golgi calcium homeostasis, as well as intra-Golgi v-SNAREs GOSR1 and BET1L, are significantly depleted in GARP-KO cells. To test if SNARE depletion is responsible for the Golgi defects in GARP deficient cells, we created and analyzed GOSR1 and BET1L KO cell lines. Since GARP-KO was more deleterious to the Golgi physiology than SNARE-KOs, we have investigated other components of intra-Golgi vesicular trafficking, particularly COPI vesicular coat and its accessory proteins. We found that COPI is partially relocalized to the ERGIC compartment in GARP-KO cells. Moreover, COPI accessory proteins GOLPH3, ARFGAP1, GBF1 were displaced from the membrane, and BIG1 was relocated to endolysosomal compartment in GARP-KO cells. We propose that the dysregulation of COPI machinery along with degradation of intra-Golgi v-SNAREs and alteration of Golgi Ca2+ homeostasis are the major driving factors for the instability of Golgi resident proteins and glycosylation defects in GARP deficient cells.

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“…Indeed, mutation of a COPI subunit can impair the maturation of cisterna as observed in yeast cells ( Matsuura-Tokita et al, 2006 ). Recent studies have described multiple COPI dependent and independent pathways operating at the Golgi (see below) to promote enzyme recycling ( Tu et al, 2008 ; Liu et al, 2018 ; Witkos et al, 2019 ; Zhao et al, 2019 ; Casler et al, 2021 ; Rizzo et al, 2021 ; Sardana et al, 2021 ), leading to a recent proposal that cisternal maturation is driven not by a single pathway but a mosaic of several likely independent recycling pathways ( Rizzo et al, 2021 ).…”

Section: Cisternal Maturation Is a Mosaic Of Recyc...mentioning

confidence: 99%

“…Similar mechanisms likely function at other levels of the Golgi complex, and other components may be involved in the recruitment of recycling adaptors or directly COPI, but this remains to be tested experimentally. Indeed, yeast Erd1 was recently found to act as a transmembrane adaptor molecule to links client enzymes to COPI coat surprising by binding to the adaptor Vps74 ( Sardana et al, 2021 ). Thus, the COPI-dependent recycling is a mosaic of at least three different pathways (one adaptor independent and two adaptor dependent pathways).…”

Section: Cisternal Maturation Is a Mosaic Of Recyc...mentioning

confidence: 99%

“…GOLPH3 gets recruited to Golgi by binding to PI(4)P through its PH domain ( Wood et al, 2009 ). While the PI(4)P-dependent recruitment of GOLPH3 to the Golgi is common across yeast and mammalian systems, in Drosophila melanogaster Rab1b has been shown to be involved in GOLPH3 recruitment ( Sechi et al, 2017 ), and similarly, Erd1 participates in the recruitment of Vps74, the GOLPH3 homolog in yeast ( Sardana et al, 2021 ). Once recruited to membranes GOLPH3 binds to enzymes that bear the Lxx(R/K) motif in their cytosolic tails and promotes their entry into recycling COPI vesicles and thus retaining the enzymes in the trans -Golgi ( Figure 4 ) ( Tu et al, 2008 ; Rizzo et al, 2021 ).…”

Section: Glycoenzyme Adapters: Central Players In Glycan Biosynthesismentioning

confidence: 99%

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Role of the Mosaic Cisternal Maturation Machinery in Glycan Synthesis and Oncogenesis

Sahu

Balakrishnan

Martino

et al. 2022

Front. Cell Dev. Biol.

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Tumorigenesis is associated with the deregulation of multiple processes, among which the glycosylation of lipids and proteins is one of the most extensively affected. However, in most cases, it remains unclear whether aberrant glycosylation is a cause, a link in the pathogenetic chain, or a mere consequence of tumorigenesis. In other cases, instead, studies have shown that aberrant glycans can promote oncogenesis. To comprehend how aberrant glycans are generated it is necessary to clarify the underlying mechanisms of glycan synthesis at the Golgi apparatus, which are still poorly understood. Important factors that determine the glycosylation potential of the Golgi apparatus are the levels and intra-Golgi localization of the glycosylation enzymes. These factors are regulated by the process of cisternal maturation which transports the cargoes through the Golgi apparatus while retaining the glycosylation enzymes in the organelle. This mechanism has till now been considered a single, house-keeping and constitutive function. Instead, we here propose that it is a mosaic of pathways, each controlling specific set of functionally related glycosylation enzymes. This changes the conception of cisternal maturation from a constitutive to a highly regulated function. In this new light, we discuss potential new groups oncogenes among the cisternal maturation machinery that can contribute to aberrant glycosylation observed in cancer cells. Further, we also discuss the prospects of novel anticancer treatments targeting the intra-Golgi trafficking process, particularly the cisternal maturation mechanism, to control/inhibit the production of pro-tumorigenic glycans.

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Golgi membrane protein Erd1 Is essential for recycling a subset of Golgi glycosyltransferases

Cited by 9 publications

References 62 publications

GARP dysfunction results in COPI displacement, depletion of Golgi v-SNAREs and calcium homeostasis proteins

GARP dysfunction results in COPI displacement, depletion of Golgi v-SNAREs and calcium homeostasis proteins

GARP complex controls Golgi physiology by stabilizing COPI machinery and Golgi v-SNAREs

Role of the Mosaic Cisternal Maturation Machinery in Glycan Synthesis and Oncogenesis

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