ERP29

Official Full Name

endoplasmic reticulum protein 29

Organism

Homo sapiens

GeneID

10961

Background

This gene encodes a protein which localizes to the lumen of the endoplasmic reticulum (ER). It is a member of the protein disulfide isomerase (PDI) protein family but lacks an active thioredoxin motif, suggesting that this protein does not function as a disulfide isomerase. The canonical protein dimerizes and is thought to play a role in the processing of secretory proteins within the ER. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

Synonyms

ERp28; ERp31; PDIA9; PDI-DB; C12orf8; HEL-S-107;

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Detailed Information

ERp29 (endoplasmic reticulum molecular chaperons 29) is a protein with a molecular weight of 29 kDa and is widely expressed in various tissues. ERp29 has two domains: an N-terminal domain and a C-terminal domain. In humans, this protein is expressed by a single gene on chromosome 12. The N-terminal domain is similar to the thioredoxin domain of protein disulfide isomerase (PDI). However, it lacks the Cys-X-X-Cys structure and cannot bind to thioredoxin, so there is no redox effect similar to PDI. The C-terminal domain is a fully helical structure containing a 4-peptide endoplasmic reticulum recovery signal sequence (KEEL) targeting the lumen of the endoplasmic reticulum, similar to the p5 subfamily of PDI. Between the two domains is a freely rotating oligo amino acid chain.

Like other important endoplasmic reticulum proteins, PDI and BiP, ERp29 is widely distributed in living organisms. It is distributed in epithelial tissues, nerve tissues, connective tissues, blood and muscle tissues. In the secretion of exuberant organs, such as the brain, pituitary, thyroid, enamel, lung, liver, adrenal gland, testis, prostate, etc., there are relatively more distribution, on the contrary, there is little distribution in the myocardium and skeletal muscle.

ERp29 Function

ERp29 can inactivate the active center of the double cysteine motif structure, thereby losing the oxidative reduction activity. ERp29 is widely distributed and abundant in mammalian tissues. It has two domains, N-terminal and C-terminal. The N-terminal domain is involved in dimerization, and the C-terminal domain is involved in substrate binding and secretion. The protein secretion function of ERp29 has been well studied at the cellular level. ERp29 is involved in and plays an important role in the unfolded protein reaction and the transport of the synthesized secreted proteins from the endoplasmic reticulum to the Golgi apparatus.

ERp29 is a new accessory protein folding/secreting endoplasmic reticulum protein that facilitates the transport of thyroglobulin and other proteins outside the cell. In many model cell and animal pathology models, the expression of ERp29 is affected by external stimuli. In the neurodegenerative disease model, ERp29 expression was decreased in the DKO mice (an age-related macular degeneration model), while ERp29 expression was increased in dopamine-treated PCI2 cells (Parkinson's model).

Chen et al. showed that in mesenchymal MDA-MB-231 cells, high expression of nuclear β-catenin activates its downstream signaling involved in cell cycle and cancer stem cell self-renewal. When ERp29 is overexpressed in this cell model, nuclear β-catenin relocalizes at its membrane bound to E-cadherin and shuts down Wnt/β-catenin signaling. At the same time, overexpression of ERp29 leads to upregulation of TCF3 and increases expression of genes involved in differentiation. Epithelial Na⁺ channels (ENaC) play a key role in the regulation of blood pressure and air volume on the airway surface. Helms et al. showed that ERp29 can regulate the regulation of ENaC.

Erp29 Figure 1. ERp29 over-expression “turns-off” activated Wnt/β-catenin signaling. (Chen, et al. 2015)

ERp29 and Tumor

ERp29 is abnormally expressed in various tumors such as breast cancer, liver cancer, prostate cancer, colorectal cancer, etc., and is associated with tumor pathological grade, recurrence, and prognosis. Studies have reported that ERp29 can play an inhibitory role in tumors and validate the anti-cancer effect of ERp29 in animal experiments. In pancreatic ductal adenocarcinoma, breast cancer, lung cancer and gallbladder carcinoma, the expression level of ERp29 in tumor tissues was negatively correlated with tumor progression. However, related studies have shown that ERp29 may be positively correlated with tumor development, ie ERp29 may play a role in promoting cancer. Therefore, there is still some controversy about whether ERp29 plays a role in promoting cancer or suppressing cancer. The expression of ERp29 may be significantly different in tumors of different states, environments, and tissues.

Recently, studies on pancreatic ductal adenocarcinoma have shown that when ERp29 expression levels are decreased, patients with pancreatic ductal adenocarcinoma have a later tumor stage, a higher rate of lymph node infiltration and metastasis, and a worse prognosis. When the homeostasis of the endoplasmic reticulum is broken, it often leads to DNA damage or oxidative stress, which may lead to tumorigenesis. ERp29 plays a role in it, but its mechanism is not yet clear. Other related studies have shown that when the level of ERp29 expression is elevated, the level of interstitial epithelialization is also significant. Expression of epithelial markers such as E-cadherin and CK-19 is increased, and expression levels of interstitial markers such as vimentin and fibronectin are decreased. The increase of epithelialization level is an important marker for the enhancement of tumor invasion and metastasis. Increased levels of ERp29 and increased MET levels reverse the EMT effect and inhibit tumor cell metastasis. Therefore, ERp29 may alter the malignant phenotype of tumor cells by affecting EMT effects.

Radiation-resistant nasopharyngeal carcinoma tissue was associated with radiation-sensitive nasopharyngeal carcinoma, and the expression of ERp29 was increased. Using gene knockout ERp29, the radiosensitivity of nasopharyngeal carcinoma cell line CNE-1 was decreased, but transfection with ERp29 caused overexpression, and the radioresistance of nasopharyngeal carcinoma cell line CNE-2 increased. The expression of ERp29 is also associated with the sensitivity of tumor cell chemotherapy. Zhan et al. reported that ERp29 expression increased the resistance of breast cancer cell line MDA-MB-231 to doxorubicin. It also reduces the apoptosis induced by the cells, but after ERp29 gene knockout, the cells are more toxic to doxorubicin.

References:

Helms, M. N., & Trac, P. (2014). Erp29, a chaperone protein ushering in new insights on ion transport regulation. focus on "erp29 regulates epithelial sodium channel functional expression by promoting channel cleavage". American Journal of Physiology Cell Physiology, 307(8), 699-700.
Chen, S., & Zhang, D. (2015). Friend or foe: endoplasmic reticulum protein 29 (erp29) in epithelial cancer. Febs Open Bio, 5(1), 91-98.
Deng, Y. J., Tang, N., Liu, C., Zhang, J. Y., An, S. L., & Peng, Y. L., et al. (2014). Clic4, erp29, and smac/diablo derived from metastatic cancer stem-like cells stratify prognostic risks of colorectal cancer. Clinical Cancer Research, 20(14), 3809-3817.
Zhang, K., Yao, H., Yang, Z., Li, D., Yang, L., & Zou, Q., et al. (2016). Comparison of ilk and erp29 expressions in benign and malignant pancreatic lesions and their clinicopathological significances in pancreatic ductal adenocarcinomas. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 18(4), 352-359.

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