Alternative titles; symbols
HGNC Approved Gene Symbol: PDIA3
Cytogenetic location: 15q15.3 Genomic coordinates (GRCh38): 15:43,746,438-43,773,278 (from NCBI)
The cDNA encoding human GRP58 was cloned independently by Bourdi et al. (1995), Koivunen et al. (1996), and Hirano et al. (1995). All reported that the gene encodes a 505-amino acid polypeptide with significant homology to human protein disulfide isomerase (PDI; 176790). Bourdi et al. (1995) noted that the sequence includes a putative nuclear localization motif and an endoplasmic reticulum (ER)-retention/retrieval motif. Koivunen et al. (1997) noted that the GRP58 sequence has 2 thioredoxin-like domains. Koivunen et al. (1997) showed by Northern blotting that GRP58 is expressed as a 2-kb message most abundantly in liver, placenta, and lung, and at lower levels in all other tissues tested.
Several laboratories have examined the functional properties of GRP58. Bourdi et al. (1995) found that the GRP58 protein had protein disulfide isomerase activity. Koivunen et al. (1996) showed that GRP58 could not substitute for the beta subunit of PDI. When coexpressed with alpha prolyl 4-hydroxylase, GRP58 did not form prolyl 4-hydroxylase tetramers, nor did it have prolyl 4-hydroxylase activity. Hirano et al. (1995) expressed human GRP58 and found that the protein had a thiol-dependent reductase activity. They showed that the expression level of GRP58 is increased after oncogenic transformation of normal rat kidney cells and NIH 3T3 cells.
Oliver et al. (1997) used a crosslinking approach to screen antisera to several ER luminal proteins in order to find proteins that interact specifically with glycoproteins in the ER. They identified GRP58 as one such protein. The authors suggested that GRP58 functions in combination with calnexin (CANX; 114217) and calreticulin (CALR; 109091) as a molecular chaperone of glycoprotein biosynthesis.
Using specific antibodies and inhibitors of PDI activity, Ellerman et al. (2006) determined that Erp57 on the surface of the mouse sperm head was involved in sperm-egg fusion. They hypothesized that thiol-disulfide exchange in gamete fusion may produce conformational changes in fusion-active proteins.
By overexpression and knockout analyses in HEK293T cells, Zhang et al. (2022) showed that CANX and CALR decreased ebolavirus entry by selectively downregulating steady-state ebolavirus GP1,2 (EBOV-GP1,2) protein in a cell type-independent manner. In the process of GP1,2 downregulation, CALR was dependent on CANX and PDIA3, whereas CANX was independent of CALR and PDIA3. Mechanistically, CANX and CALR targeted GP1,2 to autolysosomes for degradation via the ERAD machinery. A ring finger protein, RNF26 (606130), interacted with EBOV-GP1,2 and was involved in downregulation of EBOV-GP1,2, but RNF26 only supported CALR, and not CANX or PDIA3, to downregulate EBOV-GP1,2 in an E3 ubiquitin ligase activity-independent manner. Instead, CANX coopted RNF185 (620096) to interact with EBOV-GP1,2 and polyubiquitinate it on K673 in its cytoplasmic tail via ubiquitin K27 linkage for degradation.
Koivunen et al. (1997) examined the genomic organization of the GRP58 gene and reported that it is encoded on 13 exons spanning 18 kb; no similarity was found between the genomic structures of the GRP58, PDI, and thioredoxin (187700) genes.
Koivunen et al. (1997) used fluorescence in situ hybridization to map the GRP58 gene to human chromosome 15q15. They also observed that humans have a processed pseudogene, GRP58P, which is nearly identical to GRP58 and maps to chromosome 1q21.
By Southern blot analysis of an interspecific backcross, Briquet-Laugier et al. (1998) mapped the Grp58 gene to mouse chromosome 2.
PDIA3 is part of the major histocompatibility complex (MHC) class I peptide-loading complex (see TAP1; 170260), which is essential for final antigen conformation and export from the ER to the cell surface. To avoid embryonic lethality, Garbi et al. (2006) generated mice with a conditional deletion of Pdia3 in the B-cell compartment. These mice retained functional B cells with decreased MHC class I expression, as shown by flow cytometry and immunoblot analysis. Immunoprecipitation analysis showed that Pdia3 mediated recruitment of MHC class I molecules and Calr (109091) into the peptide-loading complex. Lack of Pdia3 resulted in suboptimal peptide loading and decreased T-cell activation. Garbi et al. (2006) concluded that PDIA3 is central to assembly of the peptide-loading complex and contributes quantitatively and qualitatively to MHC class I antigen presentation.
Bourdi, M., Demady, D., Martin, J. L., Jabbour, S. K., Martin, B. M., George, J. W., Pohl, L. R. cDNA cloning and baculovirus expression of the human liver endoplasmic reticulum P58: characterization as a protein disulfide isomerase isoform, but not as a protease or a carnitine acyltransferase. Arch. Biochem. Biophys. 323: 397-403, 1995. [PubMed: 7487104] [Full Text: https://doi.org/10.1006/abbi.1995.0060]
Briquet-Laugier, V., Xia, Y.-R., Rooke, K., Mehrabian, M., Lusis, A. J., Doolittle, M. H. Mapping of three members of the mouse protein disulfide isomerase family. Mammalian Genome 9: 176-177, 1998. [PubMed: 9457688] [Full Text: https://doi.org/10.1007/s003359900717]
Ellerman, D. A., Myles, D. G., Primakoff, P. A role for sperm surface protein disulfide isomerase activity in gamete fusion: evidence for the participation of ERp57. Dev. Cell 10: 831-837, 2006. [PubMed: 16740484] [Full Text: https://doi.org/10.1016/j.devcel.2006.03.011]
Garbi, N., Tanaka, S., Momburg, F., Hammerling, G. J. Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57. Nature Immun. 7: 93-102, 2006. [PubMed: 16311600] [Full Text: https://doi.org/10.1038/ni1288]
Hirano, N., Shibasaki, F., Sakai, R., Tanaka, T., Nishida, J., Yazaki, Y., Takenawa, T., Hirai, H. Molecular cloning of the human glucose-regulated protein ERp57/GRP58, a thiol-dependent reductase: identification of its secretory form and inducible expression by the oncogenic transformation. Europ. J. Biochem. 234: 336-342, 1995. [PubMed: 8529662] [Full Text: https://doi.org/10.1111/j.1432-1033.1995.336_c.x]
Koivunen, P., Helaakoski, T., Annunen, P., Veijola, J., Raisanen, S., Pihlajaniemi, T., Kivirikko, K. I. ERp60 does not substitute for protein disulphide isomerase as the beta-subunit of prolyl 4-hydroxylase. Biochem. J. 316: 599-605, 1996. [PubMed: 8687406] [Full Text: https://doi.org/10.1042/bj3160599]
Koivunen, P., Horelli-Kuitunen, N., Helaakoski, T., Karvonen, P., Jaakkola, M., Palotie, A., Kivirikko, K. I. Structures of the human gene for the protein disulfide isomerase-related polypeptide ERp60 and a processed gene and assignment of these genes to 15q15 and 1q21. Genomics 42: 397-404, 1997. [PubMed: 9205111] [Full Text: https://doi.org/10.1006/geno.1997.4750]
Oliver, J. D., van der Wal, F. J., Bulleid, N. J., High, S. Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins. Science 275: 86-88, 1997. [PubMed: 8974399] [Full Text: https://doi.org/10.1126/science.275.5296.86]
Zhang, J., Wang, B., Gao, X., Peng, C., Shan, C., Johnson, S. F., Schwartz, R. C., Zheng, Y. H. RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy. Nature Commun. 13: 6007, 2022. [PubMed: 36224200] [Full Text: https://doi.org/10.1038/s41467-022-33805-9]