Genomic Organization of the OS-9 Gene Amplified in Human Sarcomas

Kimura, Yukiko; Nakazawa, M; Tsuchiya, Naoto; Asakawa, Shuichi; Shimizu, Nobuyoshi; Yamada, Masao

doi:10.1093/oxfordjournals.jbchem.a021880

Cited by 14 publications

(11 citation statements)

References 20 publications

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“…In addition, we found that such splicing can occur also in the rat tissues, despite the fact that all 10 rat OS-9 clones (including OS-9/L1) obtained from the two-hybrid library screening, corresponded to the non-spliced variant (homologous to the isoform 1 of hOS-9). The splicing event identified in the rat and the mouse OS-9 isoforms occurs at exactly the same position (corresponding to exon 13), as in hOS-9 (16,26), suggesting that the OS-9 gene in all three species might have a conserved exon/intron organization in this region.…”

Section: Identification Of the Region In The Cytoplasmic Tail Of Meprmentioning

confidence: 84%

A Selective Interaction between OS-9 and the Carboxyl-terminal Tail of Meprin β

Litovchick

Friedmann

Shaltiel

2002

Journal of Biological Chemistry

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OS-9, a protein previously uncharacterized, was shown to interact specifically with the intracellular region of the membrane proteinase meprin ␤ found in brush border membranes of kidney and small intestine. We have shown previously that this cytoplasmic region is indispensable for the maturation of meprin ␤, which included an endoplasmic reticulum (ER)-to-Golgi translocation. We characterized OS-9 and found that it is associated with ER membranes and that it is exposed to the cytoplasm. Consistent with the kinetics of maturation of meprin ␤, OS-9 associates with meprin ␤ only transiently, coinciding with ER-to-Golgi transport of meprin ␤. The OS-9-binding site in the cytoplasmic domain of meprin ␤ overlaps the region essential for this transport. We characterized alternatively spliced forms of rat and mouse OS-9, and we found that only the nonspliced form of OS-9 binds to meprin ␤, implicating the spliced out segment in the binding, and suggesting the possible mechanism of the regulation of OS-9 function. Taken together, our results indicated that OS-9 may be involved in the ER-to-Golgi transport of meprin ␤. Ubiquitous expression of OS-9 raises the possibility that it may interact with other membrane proteins that possess the cytoplasmic moiety homologous to that of meprin ␤ during their ER-to-Golgi transition.The kinase splitting membrane proteinase was discovered as an enzyme that specifically clips and inactivates protein kinase A in the preparations of the brush border membranes of the small intestine and kidney (1, 2). Subsequently, this proteinase was shown to be identical to a ␤ subunit of meprin (3), a membrane metalloendoproteinase of the astacin family (4). We therefore refer to it here as meprin ␤. The physiological role of meprin is not established yet; however, it has been implicated in the degradation of the subset of biologically active polypeptides (4). Proteolytic activity of meprin ␤ is highly specific toward substrates that contain a cluster of acidic amino acids decorated with hydrophobic residues, such as found in the peptide hormone gastrin (5, 6).Meprins (meprin A, EC 3.4.24.18, and meprin B, EC 3.4.24.63) and oligomeric proteases are composed of two types of structurally similar subunits (␣ and ␤) that are targeted to the cell surface or are secreted (7,8). Meprin A is composed of the disulfide-bridged dimers of ␣ subunits, whereas meprin B is a heterodimer of ␣ and ␤ subunits. Higher multimeric structures formed by a non-covalent association of functionally active dimers of mouse meprin ␣ were recently observed (9). Despite the high sequence homology and similar domain structure, the ␣ and ␤ subunits of meprin undergo different posttranslational processing. Meprin ␣ (but not meprin ␤) undergoes proteolysis in the endoplasmic reticulum (ER), 1 which results in the removal of its short carboxyl-terminal cytoplasmic tail as well as a transmembrane segment and an epidermal growth factor-like domain (cf. Fig. 1A) (10). The transmembrane and cytoplasmic domains of the immature ␣ subunit of t...

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Section: Identification Of the Region In The Cytoplasmic Tail Of Meprmentioning

confidence: 84%

A Selective Interaction between OS-9 and the Carboxyl-terminal Tail of Meprin β

Litovchick

Friedmann

Shaltiel

2002

Journal of Biological Chemistry

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“…The putative risk gene OS9 consists of 15 exons and encodes four different splice variants [45,46], all of which contain a mannose 6-phosphate receptor homology domain [47]. The OS9 protein plays an important role in the ER-associated degradation of misfolded or unassembled proteins [48,49].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

Hofmann

Fischer

Nothnagel³

et al. 2012

Eur Respir J

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Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability.To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages.After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p50.0215) in the validation panel and yielded a p-value of 9.22610 -8 (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p50.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal.

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“…Cells-The OS-9 gene is composed of 15 exons (17). Alternative splicing events that conform to the GT-AG rule could generate 4 variants of the protein.…”

Section: Two Splice Variants Of Os-9 Are Expressed In Mammalianmentioning

confidence: 99%

A Dual Task for the Xbp1-responsive OS-9 Variants in the Mammalian Endoplasmic Reticulum

Bernasconi¹,

Pertel²,

Luban³

et al. 2008

Journal of Biological Chemistry

111

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Normally, non-native polypeptides are not transported through the secretory pathway. Rather, they are translocated from the endoplasmic reticulum (ER) lumen into the cytosol where they are degraded by proteasomes. Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway. OS-9 variants do not associate with folding-competent proteins. Rather, they selectively bind folding-defective ones thereby inhibiting transport of non-native conformers through the secretory pathway. The intralumenal level of OS-9.1 and OS-9.2 inversely correlates with the fraction of a folding-defective glycoprotein, the Null hong kong (NHK) variant of ␣1-antitrypsin that escapes retention-based ER quality control. OS-9 up-regulation does not affect NHK disposal, but reduction of the intralumenal level of OS-9.1 and OS-9.2 substantially delays disposal of this model substrate. OS-9.1 and OS-9.2 also associate transiently with non-glycosylated foldingdefective proteins, but association is unproductive. Finally, OS-9 activity does not require an intact mannose 6-P homology domain. Thus, OS-9.1 and OS-9.2 play a dual role in mammalian ER quality control: first as crucial retention factors for misfolded conformers, and second as promoters of protein disposal from the ER lumen.About 30% of the eukaryotic gene products are synthesized by ribosomes attached at the cytosolic face of the endoplasmic reticulum (ER) 2 (1). The nascent polypeptide chains are translocated into the ER lumen where molecular chaperones and folding enzymes assist their maturation. Native proteins are transported at their intra-or extracellular destination through the secretory pathway. The ER lumen also contains chaperones and enzymes that retain and appropriately tag terminally misfolded proteins for destruction. Due to the facility of manipulating the yeast genome, many aspects and components of ERAD have been discovered in Saccharomyces cerevisiae (2-4). Yos9p is no exception. It was initially reported that deletion of Yos9p from the yeast ER selectively inhibits degradation of glycosylated ERAD substrates (5). Subsequent work revealed that Yos9p is required for disposal of substrates with luminal folding defects, whereas it is dispensable for disposal of proteins with defects in the transmembrane and cytosolic domains (6 -10). Studies on the involvement of the mammalian ortholog OS-9 in ERAD have been hampered by data showing that OS-9 is a cytosolic protein (11). This study was followed by a series of publications in which experimental design and interpretation of the data were based on the assumption that OS-9 is a cytosolic protein (12)(13)(14).Our analysis shows that OS-9 is a N-glycosylated protein expressed in two splice variants in the ER lumen. Transcription of both OS-9 variants is enhanced upon activation of the Ire1/ Xbp1...

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Genomic Organization of the OS-9 Gene Amplified in Human Sarcomas

Cited by 14 publications

References 20 publications

A Selective Interaction between OS-9 and the Carboxyl-terminal Tail of Meprin β

A Selective Interaction between OS-9 and the Carboxyl-terminal Tail of Meprin β

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

A Dual Task for the Xbp1-responsive OS-9 Variants in the Mammalian Endoplasmic Reticulum

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