Alternative titles; symbols
HGNC Approved Gene Symbol: TXNDC5
Cytogenetic location: 6p24.3 Genomic coordinates (GRCh38): 6:7,881,517-7,910,788 (from NCBI)
TXNDC5 belongs to the protein disulfide isomerase (PDI; see 608012) family of enzymes that reside in the endoplasmic reticulum (ER) and assist in formation of disulfide bonds and in correct folding of nascent polypeptides (Knoblach et al., 2003; Sullivan et al., 2003).
By examining serial analysis of gene expression (SAGE) libraries for genes highly expressed in endothelial cells, followed by RT-PCR of total RNA isolated from human dermal microvascular endothelial cells (HDMECs), Sullivan et al. (2003) cloned TXNDC5, which they designated ENDOPDI. The deduced protein contains an N-terminal signal sequence, followed by 3 thioredoxin (TXN; 187700) motifs and a C-terminal ER retention signal (KDEL). RNase protection analysis detected higher ENDOPDI expression in human endothelial cells than in other human cells and cell lines examined. RNA dot blot analysis showed ENDOPDI expression in 20 of 72 tissues examined, with highest expression in lymph node, followed by stomach and heart. In situ hybridization revealed ENDOPDI in vasculature of human melanomas, syncytiotrophoblasts of placenta, macrophages and microvasculature of atherosclerotic plaques, and keratinocytes of hair follicles. Database analysis detected orthologs of ENDOPDI in mammals, frogs, and insects.
Knoblach et al. (2003) cloned mouse Erp46. The deduced protein has an N-terminal hydrophobic signal sequence, followed by a hydrophobic stretch, 3 thioredoxin motifs, and a C-terminal ER retention signal. Northern blot analysis showed variable Erp46 expression in 8 mouse tissues, with highest expression in liver, and no expression in skeletal muscle. Western blot analysis detected Erp46 at an apparent molecular mass of 51 kD. In fractionated mouse liver, Erp46 expression was high in ER membranes compared with whole liver homogenates. Immunohistochemical analysis of McA-RH7777 rat hepatoma cells showed colocalization of Erp46 with an ER marker throughout the ER network and in cisternae of the nuclear envelope.
Nissom et al. (2006) reported that full-length TXNDC5, which they called HCC2, contains 432 amino acids. By RT-PCR and 5-prime and 3-prime RACE, they identified a splice variant of HCC2 that was differentially upregulated in poorly defined hepatocellular carcinomas. The deduced 363-amino acid isoform has a calculated molecular mass of 40.7 kD. It is N-terminally truncated compared with full-length HCC2 and consequently lacks the predicted secretory signal and transmembrane domain. Quantitative RT-PCR detected variable expression of HCC2 in all human tissues examined, with highest expression in pancreas. HCC2 protein migrated with an apparent molecular mass of 55 kD in 2-dimensional gels.
Sullivan et al. (2003) found that hypoxia increased expression of ENDOPDI in HDMECs. Depletion of ENDOPDI via small interfering RNA increased hypoxia-induced apoptosis and necrosis in HDMECs and reduced secretion of adrenomedullin (ADM; 103275) and endothelin-1 (EDN1; 131240) and cell surface expression of CD105 (ENG; 131195), all of which protect endothelial cells from hypoxia-induced apoptosis. Knockdown of ENDOPDI had little effect on HDMEC survival in the resting state.
Knoblach et al. (2003) found that mouse Erp46 rescued a PDI-deficient yeast strain, suggesting that Erp46 functions as a PDI in mammals.
Using recombinant protein expressed in insect cells, Nissom et al. (2006) found that HCC2 showed reductase activity toward 2 interchain disulfide bonds in an in vitro insulin disulfide reduction assay.
Sullivan et al. (2003) stated that the TXNDC5 gene maps to chromosome 6p25.2.
Knoblach et al. (2003) mapped the mouse Txndc5 gene to chromosome 13.
Knoblach, B., Keller, B. O., Groenendyk, J., Aldred, S., Zheng, J., Lemire, B. D., Li, L., Michalak, M. ERp19 and ERp46, new members of the thioredoxin family of endoplasmic reticulum proteins. Molec. Cell. Proteomics 2: 1104-1119, 2003. [PubMed: 12930873] [Full Text: https://doi.org/10.1074/mcp.M300053-MCP200]
Nissom, P. M., Lo, S. L., Lo, J. C. Y., Ong, P. F., Lim, J. W. E., Ou, K., Liang, R. C., Seow, T. K., Chung, M. C. M. Hcc-2, a novel mammalian ER thioredoxin that is differentially expressed in hepatocellular carcinoma. FEBS Lett. 580: 2216-2226, 2006. [PubMed: 16574106] [Full Text: https://doi.org/10.1016/j.febslet.2006.03.029]
Sullivan, D. C., Huminiecki, L., Moore, J. W., Boyle, J. J., Poulsom, R., Creamer, D., Barker, J., Bicknell, R. EndoPDI, a novel protein-disulfide isomerase-like protein that is preferentially expressed in endothelial cells acts as a stress survival factor. J. Biol. Chem. 278: 47079-47088, 2003. [PubMed: 12963716] [Full Text: https://doi.org/10.1074/jbc.M308124200]