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Structure of the immunoregulatory sialidase NEU1.

ABSTRACT: Sialic acids linked to glycoproteins and glycolipids are important mediators of cell and protein recognition events. These sugar residues are removed by neuraminidases (sialidases). Neuraminidase-1 (sialidase-1 or NEU1) is a ubiquitously expressed mammalian sialidase located in lysosomes and on the cell membrane. Because of its modulation of multiple signaling processes, it is a potential therapeutic target for cancers and immune disorders. Genetic defects in NEU1 or in its protective protein cathepsin A (PPCA, CTSA) cause the lysosomal storage diseases sialidosis and galactosialidosis. To further our understanding of this enzyme's function at the molecular level, we determined the three-dimensional structure of murine NEU1. The enzyme oligomerizes through two self-association interfaces and displays a wide substrate-binding cavity. A catalytic loop adopts an inactive conformation. We propose a mechanism of activation involving a conformational change in this loop upon binding to its protective protein. These findings may facilitate the development of selective inhibitor and agonist therapies.

SUBMITTER: Gorelik A

PROVIDER: S-EPMC10198634 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Structure of the immunoregulatory sialidase NEU1.

Gorelik Alexei A Illes Katalin K Mazhab-Jafari Mohammad T MT Nagar Bhushan B

Science advances 20230519 20

Sialic acids linked to glycoproteins and glycolipids are important mediators of cell and protein recognition events. These sugar residues are removed by neuraminidases (sialidases). Neuraminidase-1 (sialidase-1 or NEU1) is a ubiquitously expressed mammalian sialidase located in lysosomes and on the cell membrane. Because of its modulation of multiple signaling processes, it is a potential therapeutic target for cancers and immune disorders. Genetic defects in NEU1 or in its protective protein ca ...[more]

PMID: 37205763

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Project description:Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total sialidase activity whereas PPCA expression did not. In contrast to eukaryotic sialidases, C9-BA-DANA exerted far less inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the β-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo.

Project description:BackgroundMelanoma is a kind of malignant tumor with high mortality originating from melanocytes. It is urgent to find new molecular biomarkers for prognosis and new treatment methods for melanoma. As an important molecule of sialidase family, neuraminidase-1 (NEU1) has been found to play an important role in regulating the occurrence and progression of tumors, but the role of NEU1 in melanoma is not sure.MethodsThe expression level of NEU1 in melanoma and normal tissues was evaluated by analyzing the expression data from ONCOMINE, UALCAN and GEPIA database. The mutation, copy number alteration and gene correlation of NEU1 in melanoma were evaluated by analyzing the melanoma data from cBioPortal database The protein expression levels of NEU1 were further validated by immunohistochemical (IHC) staining data from The Human Protein Atlas database. The melanoma data in TIMER 2.0 database were used to analyze the correlation between NEU1 expression and immune cell infiltration. The proliferative and migratory abilities of melanoma cells were examined by cell proliferation and migration assay in vitro and nude mice.ResultsWe discovered that NEU1 was highly expressed in melanoma samples compared with normal samples. The alteration frequency of NEU1 in melanoma patients reached 18%, and most of them were "mutation" type. The expression of NEU1 was positively correlated with the overall survival of patients with melanoma. The expression of NEU1 was positively correlated with the expression of proliferation marker CDK2 and epithelial-mesenchymal transition marker CD44 and negatively correlated with the expression of apoptosis marker CASP3 and CASP8. Moreover, the expression level of NEU1 was related to the infiltration of immune cells in melanoma. Knockdown of NEU1 attenuated the in vitro proliferative and migratory abilities of melanoma cells, as well as in vivo tumor progression of melanoma cells.ConclusionsThese findings suggest that NEU1 may play a key role in the development of melanoma and may be used as a prognostic target of melanoma.

Project description:BackgroundSialic acids are widely distributed in animal tissues, and aberrantly expressed in a variety of cancer types. High expression of sialic acid contributes to tumor aggressiveness by promoting cell proliferation, migration, angiogenesis, and metastasis. Sialidases are responsible for removal of sialic acids from glycoproteins and glycolipids.MethodsN-glycomics of bladder cancer cells were detected by MALDI-TOF mass spectrometry. Sialic acid modification in bladder cancer tissue was determined by lectin blot. The down-regulation of NEU1 in bladder cancer cells was determined by high resolution liquid chromatography mass spectrometry (HR LC-MS). The effects of sialidase NEU1 expression on proliferation and apoptosis of human bladder cancer cells were examined by western blot, RT-PCR, confocal imaging and flow cytometry. Moreover, the function of sialic acids on fibronectin-integrin α5β1 interaction were assayed by immunoprecipitation and ELISA. The importance of NEU1 in tumor formation in vivo was performed using BALB/c-nu mice. Expression of NEU1 in primary human bladder cancer tissue samples was estimated using bladder cancer tissue microarray.Results(1) Downregulation of NEU1 was primarily responsible for aberrant expression of sialic acids in bladder cancer cells. (2) Decreased NEU1 expression was correlated with bladder cancer progression. (3) NEU1 overexpression enhanced apoptosis and reduced proliferation of bladder cancer cells. (4) NEU1 disrupted FN-integrin α5β1 interaction and deactivated the Akt signaling pathway. (5) NEU1 significantly suppressed in vivo tumor formation in BALB/c-nu mice.ConclusionsOur data showed that NEU1 inhibited cancer cell proliferation, induced apoptosis, and suppressed tumor formation both in vitro and in vivo, by disrupting interaction of FN and integrin β1 and inhibiting the Akt signaling pathway. Our observations indicate that NEU1 is an important modulator of the malignant properties of bladder cancer cells, and is a potential therapeutic target for prognosis and treatment of bladder cancer. Video Abstract.

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Structure of the immunoregulatory sialidase NEU1.

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Structure of the immunoregulatory sialidase NEU1.

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