A Yeast Golgi E-type ATPase with an Unusual Membrane Topology

Zhong, Xiaotian; Guidotti, Guido

doi:10.1074/jbc.274.46.32704

Cited by 34 publications

(58 citation statements)

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“…The only apyrase of S. cerevisiae and S. pombe, Ynd1p, occurs in the yeast GA and participates in the glycosylation process (11)(12)(13). The ATPase activity of ScYnd1p is normally down-regulated by the binding of its cytoplasmic C terminus to Vma13p, a subunit of the vacuolar H ϩ -ATPase (49).…”

Section: Discussionmentioning

confidence: 99%

“…We and others have previously demonstrated (6,12,13) that UDP/GDPases play crucial roles in protein and lipid glycosylation reactions that occur in the lumen of the GA. The sugar donors for these reactions, nucleotide sugars, must first be transported by a specific transporter from the cytosol, their site of synthesis, into the lumen of the GA, where sugars are transferred by specific transferases to proteins and lipids (6,33,37).…”

Section: Discussionmentioning

confidence: 99%

“…3A). The other ORF, C33H5.14, whose gene product is NTP-1, also has five ACR domains but is more closely related to yeast and human apyrases, Ynd1p and ENTPD5 (9,11,12,13), than to UDA-1 (Fig. 3C).…”

Section: Nucleotide Hydrolyzing Activities Of C Elegans Membranes-mentioning

confidence: 99%

“…Saccharomyces cerevisiae and Schizosaccharomyces pombe each have two GA enzymes that degrade nucleoside diphosphates: ScGda1p (10) and SpGda1p (11), which are solely nucleotide diphosphatases and have preferred activity toward GDP and UDP; ScYnd1p (12,13) and SpYnd1p (11) are apyrases and use nucleoside di-and tri-phosphates as substrates. Loss of ScGDA1 function results in a drastic reduction of GDP-mannose-dependent (as opposed to lipid-linked mannose) mannosylation of proteins and lipids (10).…”

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confidence: 99%

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ire-1-dependent Transcriptional Up-regulation of a Lumenal Uridine Diphosphatase from Caenorhabditis elegans

Uccelletti

O'Callaghan

Berninsone

et al. 2004

Journal of Biological Chemistry

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Lumenal ecto-nucleoside tri-and di-phosphohydrolases (ENTPDases) of the secretory pathway of eukaryotes hydrolyze nucleoside diphosphates resulting from glycosyltransferase-mediated reactions, yielding nucleoside monophosphates. The latter are weaker inhibitors of glycosyltransferases than the former and are also antiporters for the transport of nucleotide sugars from the cytosol to the endoplasmic reticulum (ER) and Golgi apparatus (GA) lumen. Here we describe the presence of two cation-dependent nucleotide phosphohydrolase activities in membranes of Caenorhabditis elegans: one, UDA-1, is a UDP/GDPase encoded by the gene uda-1, whereas the other is an apyrase encoded by the gene ntp-1. UDA-1 shares significant amino acid sequence similarity to yeast GA Gda1p and mammalian UDP/GDPases and has a lumenal active site in vesicles displaying an intermediate density between those of the ER and GA when expressed in S. cerevisiae. NTP-1 expressed in COS-7 cells appeared to localize to the GA. The transcript of uda-1 but not those of two other C. elegans ENTPDase mRNAs (ntp-1 and mig-23) was induced up to 3.5-fold by high temperature, tunicamycin, and ethanol. The same effectors triggered the unfolded protein response as shown by the induction of expression of green fluorescent protein under the control of the BiP chaperone promoter and the UDP-glucose:glycoprotein glucosyltransferase. Up-regulation of uda-1 did not occur in ire-1-deficient mutants, demonstrating the role of this ER stress sensor in this event. We hypothesize that up-regulation of uda-1 favors hydrolysis of the glucosyltransferase inhibitory product UDP to UMP, and that the latter product then exits the lumen of the ER or pre-GA compartment in a coupled exchange with the entry of UDP-glucose, thereby further relieving ER stress by favoring protein re-glycosylation.The occurrence of the eukaryotic endomembrane system has brought forth a need for a mechanism to coordinate the metabolic flux of nucleotides, nucleotide sugars, and nucleotide sulfate between the cytosol and the lumen of secretory organelles. E-type ATPases play an important role in this function. They have been conserved through evolution with their catalytic site in the ecto-position, facing the outer surface of the plasma membrane or its topological equivalent, the lumen of intracellular organelles such as the endoplasmic reticulum (ER), 1 Golgi apparatus (GA), and lysosomes/vacuoles. These enzymes, members of the ecto-nucleoside triphosphate diphosphohydrolase (ENTPDase) family, hydrolyze nucleoside tri-and/or diphosphates in the presence of cations and share, at the amino acid sequence level, five conserved motifs called apyrase-conserved regions (ACRs) (1).Extracellular nucleotides such as ATP and ADP are intercellular signaling molecules in virtually every tissue where, modulated by ecto-apyrases, they participate in a broad range of biological processes such as the regulation of immune responses (2) and modulation of signaling by neuronal cells (3). Specifically, mammalian ENTPDase1/CD...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Nucleotide Hydrolyzing Activities Of C Elegans Membranes-mentioning

confidence: 99%

mentioning

confidence: 99%

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ire-1-dependent Transcriptional Up-regulation of a Lumenal Uridine Diphosphatase from Caenorhabditis elegans

Uccelletti

O'Callaghan

Berninsone

et al. 2004

Journal of Biological Chemistry

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“…C. elegans is an attractive model to study the relevance of intracellular E-NTPDases in alleviating ER stress and regulating protein and lipid glycosylation. Its genome encodes at least three proteins belonging to the former family of ENTPDases with sequence similarity to the Saccharomyces cerevisiae Golgi apparatus (GA) Gda1p: UDA-1 related, in substrate specificity, to the yeast Gda1p, NTP-1 an apyrase related to the yeast Ynd1p (Abeijon et al, 1993;Xiao-Dong et al, 1999;Zhong and Guidotti, 1999;Uccelletti et al, 2004) and a nucleotide diphosphatase functionally homologous to the yeast Ynd1p, encoded by the mig-23 gene. Loss of MIG-23 function results in altered gonad morphogenesis, demonstrating the importance of this enzyme (Nishiwaki et al, 2004).…”

mentioning

confidence: 99%

APY-1, a NovelCaenorhabditis elegansApyrase Involved in Unfolded Protein Response Signalling and Stress Responses

Uccelletti

Pascoli

Farina

et al. 2008

MBoC

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Protein glycosylation modulates a wide variety of intracellular events and dysfunction of the glycosylation pathway has been reported in a variety of human pathologies. Endo-apyrases have been suggested to have critical roles in protein glycosylation and sugar metabolism. However, deciphering the physiological relevance of Endo-apyrases activity has actually proved difficult, owing to their complexity and the functional redundancy within the family. We report here that a UDP/GDPase, homologous to the human apyrase Scan-1, is present in the membranes of Caenorhabditis elegans, encoded by the ORF F08C6.6 and hereinafter-named APY-1. We showed that ER stress induced by tunicamycin or high temperature resulted in increased transcription of apy-1. This increase was not observed in C. elegans mutants defective in ire-1 or atf-6, demonstrating the requirement of both ER stress sensors for up-regulation of apy-1. Depletion of APY-1 resulted in constitutively activated unfolded protein response. Defects in the pharynx and impaired organization of thin fibers in muscle cells were observed in adult worms depleted of APY-1. Some of the apy-1(RNAi) phenotypes are suggestive of premature aging, because these animals also showed accumulation of lipofuscin and reduced lifespan that was not dependent on the functioning of DAF-2, the receptor of the insulin/IGF-1 signaling pathway. INTRODUCTIONFrom observations on human diseases and mutant mice, it has become clear that glycosylation plays a major role in metazoan development (Schachter, 2004). Given the numerous physiological roles of glycoproteins, which encompass many aspects of normal cellular function and survival, the structures of glycan moieties vary markedly providing the chemical diversity required to fulfill the vast range of their biological tasks. The diversity of natural sugar structures is ultimately derived from the activities of the enzymes responsible for sugar attachment, namely glycosyltransferases, which determine the feasibility of natural product enzymatic glycodiversification. Lumenal ecto-nucleoside triand diphosphohydrolases (E-NTPDases) of the secretory pathway of eukaryotes hydrolyzes the nucleoside diphosphates (NDPs) generated by glycosyltransferases. The resulting nucleoside monophosphates (NMPs) are weaker inhibitors of glycosyltransferases than NDPs. NMPs also serve as antiporters in the transport of nucleotide-sugars from the cytosol to the lumen of the endoplasmic reticulum (ER) and Golgi apparatus. Glycosylation plays an important role in the biogenesis of secreted and transmembrane proteins and an elaborate mechanism ensure that only properly folded and assembled proteins exit the ER, a process termed "quality control."However, The ER's capacity to process proteins is relatively limited and the stress caused by accumulation of unfolded and misfolded proteins (ER stress) contributes to a number of important human diseases (Zhang and Kaufman, 2006). Cells respond to ER stress by activating the unfolded protein response (UPR), which limits new pr...

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Biology of the adenovirus E4orf4 protein: from virus infection to cancer cell death

Kleinberger

2019

FEBS Letters

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The adenovirus (Ad) early region 4 open reading frame 4 (E4orf4) protein is a small 14‐kDa polypeptide endowed with important viral regulatory functions. Although deletion of E4orf4 does not have a major effect on Ad replication due to redundancy among many Ad proteins, E4orf4 provides several functions that improve viral replication. E4orf4 contributes to temporal regulation of virus infection by downregulating early viral gene expression and by altering splicing patterns of Ad mRNAs. It also optimizes the cellular environment for Ad replication by activating the mammalian target of rapamycin pathway to increase viral protein production and by impacting the cell cycle. In addition, E4orf4 participates in the inhibition of the host DNA damage response, promoting the ability of Ad to counteract this antiviral defense mechanism. To fulfill these functions, E4orf4 interacts with numerous cellular proteins, including the major E4orf4 partner, protein phosphatase 2A (PP2A). When expressed alone, outside the context of virus infection, E4orf4 induces an evolutionarily conserved, caspase‐independent, cancer‐selective cell death with many interesting characteristics. This review critically describes E4orf4’s contribution to Ad infection and cancer‐cell death.

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A Yeast Golgi E-type ATPase with an Unusual Membrane Topology

Cited by 34 publications

References 57 publications

ire-1-dependent Transcriptional Up-regulation of a Lumenal Uridine Diphosphatase from Caenorhabditis elegans

ire-1-dependent Transcriptional Up-regulation of a Lumenal Uridine Diphosphatase from Caenorhabditis elegans

APY-1, a NovelCaenorhabditis elegansApyrase Involved in Unfolded Protein Response Signalling and Stress Responses

Biology of the adenovirus E4orf4 protein: from virus infection to cancer cell death

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