NEU1

Official Full Name

neuraminidase 1

Organism

Homo sapiens

GeneID

4758

Background

The protein encoded by this gene is a lysosomal enzyme that cleaves terminal sialic acid residues from substrates such as glycoproteins and glycolipids. In the lysosome, this enzyme is part of a heterotrimeric complex together with beta-galactosidase and cathepsin A (the latter is also referred to as 'protective protein'). Mutations in this gene can lead to sialidosis, a lysosomal storage disease that can be type 1 (cherry red spot-myoclonus syndrome or normosomatic type), which is late-onset, or type 2 (the dysmorphic type), which occurs at an earlier age with increased severity. [provided by RefSeq, Jul 2008]

Synonyms

NEU; NANH; SIAL1;

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Detailed Information

Sialic acid is widely present in living organisms and is often present at the end of the sugar chain of sugar complexes. It is essential for the development of tissues and organs, especially the brain, and is closely related to the occurrence and development of various diseases. When sialic acid is hydrolyzed by sialidase, the conformation of the glycoconjugate can be altered to regulate the biological function of the relevant factor. Sialidase is widely present in living organisms. Four sialidases have been found in mammals. They are named Neu1, Neu2, Neu3 and Neu4 depending on the splicing substrate and the distribution within the cell. Among them, the study of Neu1 is more in-depth.

The Biological Function of NEU1

Neu1 is expressed in lysosomes, and it needs to form a complex with protective protein/cathepsin A (PPCA) and β-gal (β-galactosidase) to exert its function. The activity of PPCA is not necessary for the activity of Neu1 and β-gal enzymes. It acts as a molecular chaperone to help Neu1 fold, stabilize, oligomerize and activate. When PPCA depolymerizes with Neu1, it can cause compound dissociation and Neu1 inactivation.

Elastin-binding protein (EBP) is a β-gal cleavage mutant that forms a complex with Neu1 and PPCA on the cell surface. Cell surface Neu1 activity is a prerequisite for the release of elastin. Sialidase inhibitors inhibit the assembly of elastin fibers in human dermal fibroblasts, aortic smooth muscle cells, and the formation of elastic fibers, which can be successfully reversed when exogenously overexpressing Neu1.

Neu1-mediated Cellular Receptor Signaling

EGFR is a cell surface receptor glycoprotein belonging to the epidermal growth factor family and has receptor tyrosine kinases activity that can be recognized by a variety of ligands. On the cell surface, MUC1 regulates the EGFR signaling pathway by interacting with EGFR. Using immunohistochemistry, it was found that in triple-negative breast cancer, the expression of EGFR was significantly increased compared with the normal group, and the expression of Neu1 was down-regulated, and the degree of autophagy in cancer tissues was significantly lower than that in normal tissues. By analyzing their correlation, it was found that EGFR-MUC1-Neu1 complex abnormality caused by decreased autophagy in triple-negative breast cancer, leading to changes in its related signaling pathway, indicating that Neu1 is involved in lysosomal pathway-mediated autophagy and endocytosis.

Figure 1. Neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) cross-talk in alliance with G proteincoupled receptor(s) (GPCR) regulates receptor tyrosine kinases (RTKs). (Haxho, F., et al. 2015)

NEU1 and Tumor

The change in the expression level of Neu1 is also related to the degree of deterioration of various tumors. Neu1 can inhibit the extracellular secretion of lysosome by shearing the sialic acid modification of LAMP1. As the extracellular secretion of lysosomes in tumor cells is aggravated, the secretion of hydrolases and exosomes increases, which promotes the invasion of the matrix and the spread of invasive signals and the clearance of chemotherapy drugs. In the mouse model of Arf knockout (Arf -/-), it was found that low expression of Neu1 (Neu1+/-) facilitates the formation of invasive pleomorphic sarcoma, promotes epithelial and mesenchymal cell marker molecules, and increases the expression of the extracellular secreted factors LAMP1 and Myosin-11. These characteristics are similar to those of human metastatic pleomorphic sarcoma, suggesting that lysosomal regulatory pathways are critical for tumor development and drug resistance. Thus, it has been proposed to inhibit tumor invasion and drug resistance by inhibiting the extracellular secretion of lysosomes.

Overexpression of Neu1 in malignant melanoma cells B16-BL6, cells showed inhibition of lung metastasis and tumor formation, cell growth retardation, and increased sensitivity to apoptosis. When the colon cancer cell line HT29 overexpressing Neu1 was injected into the spleen of mice, its ability to metastasize to the liver was significantly lower than that of the control group, and it was found that Neu1 can cause its phosphorylation down-regulation by hydrolyzing sialic acid on Integrin β4, which in turn inhibits FAK (focal adhesion kinase) activity and ERK1/2 (extracellular signal-regulated kinase 1/2) signaling pathway.

References:

Haxho, F. , Neufeld, R. J. , & Szewczuk, M. R. . (2015). Neuraminidase-1: a novel therapeutic target in multistage tumorigenesis. Oncotarget, 7(26).
D'Azzo, A., Machado, E., & Annunziata, I. (2015). Pathogenesis, emerging therapeutic targets and treatment in sialidosis. Expert Opinion on Orphan Drugs, 3(5), 491.
Kwak, J. E. , Son, M. Y. , Son, Y. S. , Son, M. J. , & Cho, Y. S. . (2015). Biochemical and molecular characterization of novel mutations in glb1 and neu1 in patient cells with lysosomal storage disorders. Biochemical and Biophysical Research Communications, 457(4), 554-560.

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