Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

Barlowe, Charles; Miller, Elizabeth A.

doi:10.1534/genetics.112.142810

Cited by 257 publications

(253 citation statements)

References 343 publications

(401 reference statements)

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“…Anterograde transport of proteins from the ER to the Golgi occurs through their incorporation into transport vesicles that bud from ER membranes (39,40). Methods that reconstitute in vitro formation of ER-derived transport vesicles have been established (30,31).…”

Section: Resultsmentioning

confidence: 99%

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgUbiA prenyltransferase domain-containing protein-1 (UBIAD1) belongs to the UbiA superfamily of integral membrane prenyltransferases (1). These enzymes contain 8-10 transmembrane helices and catalyze transfer of isoprenyl groups to aromatic acceptors, producing a wide range of molecules such as ubiquinones, hemes, chlorophylls, vitamin E, and vitamin K. In animals, UBIAD1 catalyzes transfer of the 20-carbon geranylgeranyl moiety from geranylgeranyl pyrophosphate (GGpp) to menadione released from plant-derived phylloquinone, thereby generating the vitamin K 2 subtype, menaquinone-4 (MK-4) (2, 3).Mutations in the UBIAD1 gene are associated with Schnyder corneal dystrophy (SCD), an autosomal dominant human eye disease characterized by progressive opacification of the cornea, owing to abnormal accumulation of cholesterol and other lipids (4,5). Systemic dyslipidemia appears to be associated with some, but not all, SCD cases (6, 7). Missense mutations that alter 20 amino acid residues in UBIAD1 have been identified in 50 SCD families (8, 9). Several of these altered amino acids reside within the active site of UBIAD1 (10, 11). A link between UBIAD1 and cholesterol metabolism was first provided by coimmunoprecipitation studies that showed an association of UBIAD1 with the cholesterol biosynthetic enzyme, HMGCoA reductase (8). More recently, we showed that UBIAD1 inhibits sterol-accelerated endoplasmic reticulum (ER)-associated degradation (ERAD) of reductase (12), one of several feedback mechanisms that converge on the enzyme to maintain cholesterol homeostasis (13).Abstract UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K 2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1. Here, we further characterize geranylgeranyl-regulated transport of UBIAD1.

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Section: Resultsmentioning

confidence: 99%

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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“…These vesicles are generated by polymerization of the cytosolic coat protein complex II (COPII), which locally bends the ER membrane at specifi c domains called ER exit sites (ERESs). For effi cient ER export, most secretory proteins are actively captured by direct or indirect interactions with the COPII coat to be fi rst concentrated at ERESs and then packaged into nascent COPII vesicles ( 8 ). At fi rst, it was believed that all secretory proteins travel together in the same COPII vesicles to the Golgi, from where they are sorted to their fi nal destinations.…”

Section: Export From the Ermentioning

confidence: 99%

Trafficking of glycosylphosphatidylinositol anchored proteins from the endoplasmic reticulum to the cell surface

Muñiz

Riezman

2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org vesicular traffi cking events ( 1 ). Many secretory proteins that are delivered to the cell surface, including a wide diversity of receptors, adhesion molecules, and enzymes, are attached to the external leafl et of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor ( 2 ). The core structure of the GPI anchor precursor is largely conserved in evolution and consists of a phospholipid moiety (acylphosphatidylinositol) with a glycan backbone [Man4-(EtNP)Man3-(EtNP)Man2-(EtNP)Man1-GlcN], where EtNP is a side-branch ethanolamine-phosphate, Man is mannose (the numbers represent the positions of the Man in the anchor), and GlcN is glucosamine). Once the GPI anchor precursor has been made by a series of sequential reactions at the ER membrane, it is then attached en bloc in the ER lumen by a GPI-transamidase complex to newly synthesized proteins containing a GPI attachment signal sequence at their C terminus. Immediately after attachment to the protein, the structure of the lipid and glycan parts of the GPI anchor are modifi ed by several remodeling enzymes ( 3 ). This remodeling process converts the GPI anchor into a transport signal that actively promotes the ER export of GPI-anchored proteins (GPI-APs) to the Golgi apparatus, from where they are subsequently routed to their functional site of residence, the plasma membrane.The presence of the GPI anchor confers to GPI-APs a unique mode of membrane association within the lumen of secretory organelles that leads them to be transported The eukaryotic secretory pathway is responsible for the synthesis and delivery of correctly assembled proteins from the endoplasmic reticulum (ER) to their fi nal functional destination, the extracellular media, the plasma membrane, or the endocytic/secretory membrane system. The vast majority of proteins are transported by a series of specifi c Abstract In eukaryotes, many cell surface proteins are attached to the plasma membrane via a glycolipid glycosylphosphatidylinositol (GPI) anchor. GPI-anchored proteins (GPI-APs) receive the GPI anchor as a conserved posttranslational modifi cation in the lumen of the endoplasmic reticulum (ER). After anchor attachment, the GPI anchor is structurally remodeled to function as a transport signal that actively triggers the delivery of GPI-APs from the ER This work was supported by grants

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“…The process of N‐glycosylation consists of a covalent linkage of a specific oligosaccharide (Glc 3 Man 9 GlcNAc 2 ) to a nascent protein. Once the oligosaccharide is transferred, several subsequent steps of maturation occur along the secretory pathway 3. The four class I α‐1,2 mannosidases in humans are ER α‐mannosidase I (MAN1B1) and three Golgi α1,2‐mannosidases (Golgi α‐mannosidase IA [MAN1A1], Golgi α‐mannosidase IB [MAN1A2], and Golgi α‐mannosidase IC [MAN1C1]).…”

Section: Introductionmentioning

confidence: 99%

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Hsiao

Yang

et al. 2017

Hepatology Communications

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α‐1,2 mannosidases, key enzymes in N‐glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α‐1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α‐1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α‐fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1‐overexpressing cells but decreased in MAN1C1‐overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1‐activated genes. Using the MAN1A1 liver‐specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230‐247)

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Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

Cited by 257 publications

References 343 publications

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Trafficking of glycosylphosphatidylinositol anchored proteins from the endoplasmic reticulum to the cell surface

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

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