Journal articles: 'Sialidase NEU4'

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Manzoni, Marta, Paolo Colombi, Nadia Papini, Luana Rubaga, Natascia Tiso, Augusto Preti, Bruno Venerando, et al. "Molecular cloning and biochemical characterization of sialidases from zebrafish (Danio rerio)." Biochemical Journal 408, no. 3 (November 28, 2007): 395–406. http://dx.doi.org/10.1042/bj20070627.

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Sialidases remove sialic acid residues from various sialo-derivatives. To gain further insights into the biological roles of sialidases in vertebrates, we exploited zebrafish (Danio rerio) as an animal model. A zebrafish transcriptome- and genome-wide search using the sequences of the human NEU polypeptides as templates revealed the presence of seven different genes related to human sialidases. neu1 and neu4 are the putative orthologues of the mammalian sialidases NEU1 and NEU4 respectively. Interestingly, the remaining genes are organized in clusters located on chromosome 21 and are all more closely related to mammalian sialidase NEU3. They were thus named neu3.1, neu3.2, neu3.3, neu3.4 and neu3.5. Using RT–PCR (reverse transcription–PCR) we detected transcripts for all genes, apart from neu3.4, and whole-mount in situ hybridization experiments show a localized expression pattern in gut and lens for neu3.1 and neu4 respectively. Transfection experiments in COS7 (monkey kidney) cells demonstrate that Neu3.1, Neu3.2, Neu3.3 and Neu4 zebrafish proteins are sialidase enzymes. Neu3.1, Neu3.3 and Neu4 are membrane-associated and show a very acidic pH optimum below 3.0, whereas Neu3.2 is a soluble sialidase with a pH optimum of 5.6. These results were further confirmed by subcellular localization studies carried out using immunofluorescence. Moreover, expression in COS7 cells of these novel zebrafish sialidases (with the exception of Neu3.2) induces a significant modification of the ganglioside pattern, consistent with the results obtained with membrane-associated mammalian sialidases. Overall, the redundancy of sialidases together with their expression profile and their activity exerted on gangliosides of living cells indicate the biological relevance of this class of enzymes in zebrafish.

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Sodeoka, Mikiko, Go Hirai, Toru Watanabe, and Taeko Miyagi. "A strategy for constructing C-sialosides based on Ireland-Claisen rearrangement and its application for synthesis of CF2-linked ganglioside GM4 analog." Pure and Applied Chemistry 81, no. 2 (January 1, 2009): 205–15. http://dx.doi.org/10.1351/pac-con-08-09-14.

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Sialidase-resistant ganglioside analogs having similar biological activities to natural gangliosides are expected to be important probes for clarifying the biological functions of gangliosides. Focusing on difluoromethylene-linked (CF2-linked) and methylene-linked (CH2-linked) α(2,3)sialylgalactose as a core structure of sialidase-resistant ganglioside mimics, we have developed novel, stereocontrolled, and efficient methodologies to synthesize C-sialosides based on Ireland-Claisen rearrangement. These methods were employed to synthesize CF2-linked GM4. The CF2-linked GM4 inhibited human sialidases NEU2 and NEU4 with IC50 values of 754 and 930 μM, respectively, and strongly inhibited human lymphocyte proliferation in the same concentration range as natural GM4.

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Zhang, Jun-Yuan, Qian-Qian Chen, Jia Li, Lei Zhang, and Lian-Wen Qi. "Neuraminidase 1 and its Inhibitors from Chinese Herbal Medicines: An Emerging Role for Cardiovascular Diseases." American Journal of Chinese Medicine 49, no. 04 (January 2021): 843–62. http://dx.doi.org/10.1142/s0192415x21500403.

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Neuraminidase, also known as sialidase, is ubiquitous in animals and microorganisms. It is predominantly distributed in the cell membrane, cytoplasmic vesicles, and lysosomes. Neuraminidase generally recognizes the sialic acid glycosidic bonds at the ends of glycoproteins or glycolipids and enzymatically removes sialic acid. There are four types of neuraminidases, named as Neu1, Neu2, Neu3, and Neu4. Among them, Neu1 is the most abundant in mammals. Recent studies have revealed the involvement of Neu1 in several diseases, including cardiovascular diseases, diabetes, cancers, and neurological disorders. In this review, we center the attention to the role of Neu1 in cardiovascular diseases, including atherosclerosis, ischemic myocardial injury, cerebrovascular disease, congenital heart disease, and pulmonary embolism. We also summarize inhibitors from Chinese herbal medicines (CHMs) in inhibiting virus neuraminidase or human Neu1. Many Chinese herbs and Chinese herb preparations, such as Lonicerae Japonicae Flos, Scutellariae Radix, Yupingfeng San, and Huanglian Jiedu Decoction, have neuraminidase inhibitory activity. We hope to highlight the emerging role of Neu1 in humans and potentially titillate interest for further studies in this area.

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Yamaguchi, Kazunori, Keiko Hata, Koichi Koseki, Kazuhiro Shiozaki, Hirotoshi Akita, Tadashi Wada, Setsuko Moriya, and Taeko Miyagi. "Evidence for mitochondrial localization of a novel human sialidase (NEU4)." Biochemical Journal 390, no. 1 (August 9, 2005): 85–93. http://dx.doi.org/10.1042/bj20050017.

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Based on the human cDNA sequence predicted to represent the NEU4 sialidase gene in public databases, a cDNA covering the entire coding sequence was isolated from human brain and expressed in mammalian cells. The cDNA encodes two isoforms: one possessing an N-terminal 12-amino-acid sequence that is predicted to be a mitochondrial targeting sequence, and the other lacking these amino acids. Expression of the isoforms is tissuespecific, as assessed by reverse transcription–PCR. Brain, muscle and kidney contained both isoforms; liver showed the highest expression, and the short form was predominant in this organ. In transiently transfected COS-1 cells, enzyme activity was markedly increased with gangliosides as well as with glycoproteins and oligosaccharides as substrates compared with the control levels. This differs from findings with other human sialidases. Although the isoforms were not distinguishable with regard to substrate specificity, they exhibited differential subcellular localizations. Immunofluorescence microscopy and biochemical fractionation demonstrated that an exogenously expressed haemagglutinin-tagged long form of NEU4 was concentrated in mitochondria in several human culture cell types, whereas the short form was present in intracellular membranes, indicating that the sequence comprising the N-terminal 12 amino acid residues acts as a targeting signal for mitochondria. Co-localization of the long form to mitochondria was further supported by efficient targeting of the N-terminal region fused to enhanced green fluorescent protein, and by the targeting failure of a mutant with an amino acid substitution in this region. NEU4 is possibly involved in regulation of apoptosis by modulation of ganglioside GD3, which accumulates in mitochondria during apoptosis and is the best substrate for the sialidase.

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SEYRANTEPE, Volkan, and Murat DELMAN. "Characterization of the human sialidase Neu4 gene promoter." TURKISH JOURNAL OF BIOLOGY 38 (2014): 574–80. http://dx.doi.org/10.3906/biy-1401-63.

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6

Timur, Zehra Kevser, Orhan Kerim Inci, Secil Akyildiz Demir, and Volkan Seyrantepe. "Sialidase neu4 deficiency is associated with neuroinflammation in mice." Glycoconjugate Journal 38, no. 6 (October 23, 2021): 649–67. http://dx.doi.org/10.1007/s10719-021-10017-9.

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7

Silvestri, I., F. Testa, R. Zappasodi, C. W. Cairo, Y. Zhang, B. Lupo, R. Galli, M. Di Nicola, B. Venerando, and C. Tringali. "Sialidase NEU4 is involved in glioblastoma stem cell survival." Cell Death & Disease 5, no. 8 (August 2014): e1381-e1381. http://dx.doi.org/10.1038/cddis.2014.349.

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8

Comelli, Elena M., Margarida Amado, Sarah R. Lustig, and James C. Paulson. "Identification and expression of Neu4, a novel murine sialidase." Gene 321 (December 2003): 155–61. http://dx.doi.org/10.1016/j.gene.2003.08.005.

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9

Seyrantepe, Volkan, Maryssa Canuel, Stéphane Carpentier, Karine Landry, Stéphanie Durand, Feng Liang, Jibin Zeng, et al. "Mice deficient in Neu4 sialidase exhibit abnormal ganglioside catabolism and lysosomal storage." Human Molecular Genetics 17, no. 11 (February 11, 2008): 1556–68. http://dx.doi.org/10.1093/hmg/ddn043.

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10

Shiozaki, Kazuhiro, Sena Ryuzono, Naoto Matsushita, Asami Ikeda, Kazuki Takeshita, Petros Kingstone Chigwechokha, Masaharu Komatsu, and Taeko Miyagi. "Molecular cloning and biochemical characterization of medaka (Oryzias latipes) lysosomal neu4 sialidase." Fish Physiology and Biochemistry 40, no. 5 (April 18, 2014): 1461–72. http://dx.doi.org/10.1007/s10695-014-9940-9.

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11

Magesh, Sadagopan, Tohru Suzuki, Taeko Miyagi, Hideharu Ishida, and Makoto Kiso. "Homology modeling of human sialidase enzymes NEU1, NEU3 and NEU4 based on the crystal structure of NEU2: Hints for the design of selective NEU3 inhibitors." Journal of Molecular Graphics and Modelling 25, no. 2 (October 2006): 196–207. http://dx.doi.org/10.1016/j.jmgm.2005.12.006.

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12

Shiozaki, Kazuhiro, Kazunori Yamaguchi, Kohta Takahashi, Setsuko Moriya, and Taeko Miyagi. "Regulation of Sialyl Lewis Antigen Expression in Colon Cancer Cells by Sialidase NEU4." Journal of Biological Chemistry 286, no. 24 (April 26, 2011): 21052–61. http://dx.doi.org/10.1074/jbc.m111.231191.

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13

Yamanami, Hideaki, Kazuhiro Shiozaki, Tadashi Wada, Kazunori Yamaguchi, Takuji Uemura, Yoichiro Kakugawa, Tsuneaki Hujiya, and Taeko Miyagi. "Down-regulation of sialidase NEU4 may contribute to invasive properties of human colon cancers." Cancer Science 98, no. 3 (March 2007): 299–307. http://dx.doi.org/10.1111/j.1349-7006.2007.00403.x.

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14

Honda, Akinobu, Oki Hayasaka, Kenjiro Mio, Koji Fujimura, Tomonari Kotani, Masaharu Komatsu, and Kazuhiro Shiozaki. "The involvement of Nile tilapia (Oreochromis niloticus) Neu4 sialidase in neural differentiation during early ontogenesis." Biochimie 185 (June 2021): 105–16. http://dx.doi.org/10.1016/j.biochi.2021.03.008.

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15

Seyrantepe, Volkan, Karine Landry, Stéphanie Trudel, Jacob A. Hassan, Carlos R. Morales, and Alexey V. Pshezhetsky. "Neu4, a Novel Human Lysosomal Lumen Sialidase, Confers Normal Phenotype to Sialidosis and Galactosialidosis Cells." Journal of Biological Chemistry 279, no. 35 (June 22, 2004): 37021–29. http://dx.doi.org/10.1074/jbc.m404531200.

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16

Monti, E., M. T. Bassi, R. Bresciani, S. Civini, G. L. Croci, N. Papini, M. Riboni, et al. "Molecular cloning and characterization of NEU4, the fourth member of the human sialidase gene family." Genomics 83, no. 3 (March 2004): 445–53. http://dx.doi.org/10.1016/j.ygeno.2003.08.019.

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17

Finlay, Trisha M., Samar Abdulkhalek, Alanna Gilmour, Christina Guzzo, Preethi Jayanth, Schammim Ray Amith, Katrina Gee, Rudi Beyaert, and Myron R. Szewczuk. "Thymoquinone-induced Neu4 sialidase activates NFκB in macrophage cells and pro-inflammatory cytokines in vivo." Glycoconjugate Journal 27, no. 6 (August 2010): 583–600. http://dx.doi.org/10.1007/s10719-010-9302-5.

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18

Karhadkar, Tejas R., Wensheng Chen, Darrell Pilling, and Richard H. Gomer. "Inhibitors of the Sialidase NEU3 as Potential Therapeutics for Fibrosis." International Journal of Molecular Sciences 24, no. 1 (December 23, 2022): 239. http://dx.doi.org/10.3390/ijms24010239.

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Fibrosing diseases are a major medical problem, and are associated with more deaths per year than cancer in the US. Sialidases are enzymes that remove the sugar sialic acid from glycoconjugates. In this review, we describe efforts to inhibit fibrosis by inhibiting sialidases, and describe the following rationale for considering sialidases to be a potential target to inhibit fibrosis. First, sialidases are upregulated in fibrotic lesions in humans and in a mouse model of pulmonary fibrosis. Second, the extracellular sialidase NEU3 appears to be both necessary and sufficient for pulmonary fibrosis in mice. Third, there exist at least three mechanistic ways in which NEU3 potentiates fibrosis, with two of them being positive feedback loops where a profibrotic cytokine upregulates NEU3, and the upregulated NEU3 then upregulates the profibrotic cytokine. Fourth, a variety of NEU3 inhibitors block pulmonary fibrosis in a mouse model. Finally, the high sialidase levels in a fibrotic lesion cause an easily observed desialylation of serum proteins, and in a mouse model, sialidase inhibitors that stop fibrosis reverse the serum protein desialylation. This then indicates that serum protein sialylation is a potential surrogate biomarker for the effect of sialidase inhibitors, which would facilitate clinical trials to test the exciting possibility that sialidase inhibitors could be used as therapeutics for fibrosis.

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19

Hata, Keiko, Koichi Koseki, Kazunori Yamaguchi, Setsuko Moriya, Yasuo Suzuki, Sangchai Yingsakmongkon, Go Hirai, Mikiko Sodeoka, Mark von Itzstein, and Taeko Miyagi. "Limited Inhibitory Effects of Oseltamivir and Zanamivir on Human Sialidases." Antimicrobial Agents and Chemotherapy 52, no. 10 (August 11, 2008): 3484–91. http://dx.doi.org/10.1128/aac.00344-08.

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ABSTRACT Oseltamivir (Tamiflu) and zanamivir (Relenza), two extensively used clinically effective anti-influenza drugs, are viral sialidase (also known as neuraminidase) inhibitors that prevent the release of progeny virions and thereby limit the spread of infection. Recently mortalities and neuropsychiatric events have been reported with the use of oseltamivir, especially in pediatric cases in Japan, suggesting that these drugs might also inhibit endogenous enzymes involved in sialic acid metabolism, including sialidase, sialyltransferase, and CMP-synthase, in addition to their inhibitory effects on the viral sialidase. The possible inhibition could account for some of the rare side effects of oseltamivir. However, there has been little direct evidence in regard to the sensitivities of animal sialidases to these drugs. Here, we examined whether these inhibitors might indeed affect the activities of human sialidases, which differ in primary structures and enzyme properties but possess tertiary structures similar to those of the viral enzymes. Using recombinant enzymes corresponding to the four human sialidases identified so far, we found that oseltamivir carboxylate scarcely affected the activities of any of the sialidases, even at 1 mM, while zanamivir significantly inhibited the human sialidases NEU3 and NEU2 in the micromolar range (Ki , 3.7 ± 0.48 and 12.9 ± 0.07 μM, respectively), providing a contrast to the low nanomolar concentrations at which these drugs block the activity of the viral sialidases.

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20

Bigi, Alessandra, Cristina Tringali, Matilde Forcella, Alessandra Mozzi, Bruno Venerando, Eugenio Monti, and Paola Fusi. "A proline-rich loop mediates specific functions of human sialidase NEU4 in SK-N-BE neuronal differentiation." Glycobiology 23, no. 12 (September 12, 2013): 1499–509. http://dx.doi.org/10.1093/glycob/cwt078.

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21

Takahashi, Kohta, Junya Mitoma, Masahiro Hosono, Kazuhiro Shiozaki, Chihiro Sato, Kazunori Yamaguchi, Ken Kitajima, et al. "Sialidase NEU4 Hydrolyzes Polysialic Acids of Neural Cell Adhesion Molecules and Negatively Regulates Neurite Formation by Hippocampal Neurons." Journal of Biological Chemistry 287, no. 18 (March 5, 2012): 14816–26. http://dx.doi.org/10.1074/jbc.m111.324186.

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22

Shiozaki, Kazuhiro, Koichi Koseki, Kazunori Yamaguchi, Momo Shiozaki, Hisashi Narimatsu, and Taeko Miyagi. "Developmental Change of Sialidase Neu4 Expression in Murine Brain and Its Involvement in the Regulation of Neuronal Cell Differentiation." Journal of Biological Chemistry 284, no. 32 (June 8, 2009): 21157–64. http://dx.doi.org/10.1074/jbc.m109.012708.

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23

Bigi, Alessandra, Lavinia Morosi, Chiara Pozzi, Matilde Forcella, Guido Tettamanti, Bruno Venerando, Eugenio Monti, and Paola Fusi. "Human sialidase NEU4 long and short are extrinsic proteins bound to outer mitochondrial membrane and the endoplasmic reticulum, respectively." Glycobiology 20, no. 2 (September 30, 2009): 148–57. http://dx.doi.org/10.1093/glycob/cwp156.

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24

Honda, Akinobu, Petros Kingstone Chigwechokha, Yuko Kamada-Futagami, Masaharu Komatsu, and Kazuhiro Shiozaki. "Unique nuclear localization of Nile tilapia ( Oreochromis niloticus ) Neu4 sialidase is regulated by nuclear transport receptor importin α/β." Biochimie 149 (June 2018): 92–104. http://dx.doi.org/10.1016/j.biochi.2018.04.003.

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25

Jansen, A. J. Gerard, Emma C. Josefsson, Viktoria Rumjantseva, Qiyong Peter Liu, Hervé Falet, Wolfgang Bergmeier, Stephen M. Cifuni, et al. "Desialylation accelerates platelet clearance after refrigeration and initiates GPIbα metalloproteinase-mediated cleavage in mice." Blood 119, no. 5 (February 2, 2012): 1263–73. http://dx.doi.org/10.1182/blood-2011-05-355628.

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AbstractWhen refrigerated platelets are rewarmed, they secrete active sialidases, including the lysosomal sialidase Neu1, and express surface Neu3 that remove sialic acid from platelet von Willebrand factor receptor (VWFR), specifically the GPIbα subunit. The recovery and circulation of refrigerated platelets is greatly improved by storage in the presence of inhibitors of sialidases. Desialylated VWFR is also a target for metalloproteinases (MPs), because GPIbα and GPV are cleaved from the surface of refrigerated platelets. Receptor shedding is inhibited by the MP inhibitor GM6001 and does not occur in Adam17ΔZn/ΔZn platelets expressing inactive ADAM17. Critically, desialylation in the absence of MP-mediated receptor shedding is sufficient to cause the rapid clearance of platelets from circulation. Desialylation of platelet VWFR therefore triggers platelet clearance and primes GPIbα and GPV for MP-dependent cleavage.

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MONTI, Eugenio, Maria T. BASSI, Nadia PAPINI, Mirko RIBONI, Marta MANZONI, Bruno VENERANDO, Gianluigi CROCI, et al. "Identification and expression of NEU3, a novel human sialidase associated to the plasma membrane." Biochemical Journal 349, no. 1 (June 26, 2000): 343–51. http://dx.doi.org/10.1042/bj3490343.

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Several mammalian sialidases have been described so far, suggesting the existence of numerous polypeptides with different tissue distributions, subcellular localizations and substrate specificities. Among these enzymes, plasma-membrane-associated sialidase(s) have a pivotal role in modulating the ganglioside content of the lipid bilayer, suggesting their involvement in the complex mechanisms governing cell-surface biological functions. Here we describe the identification and expression of a human plasma-membrane-associated sialidase, NEU3, isolated starting from an expressed sequence tag (EST) clone. The cDNA for this sialidase encodes a 428-residue protein containing a putative transmembrane helix, a YRIP (single-letter amino acid codes) motif and three Asp boxes characteristic of sialidases. The polypeptide shows high sequence identity (78%) with the membrane-associated sialidase recently purified and cloned from Bos taurus. Northern blot analysis showed a wide pattern of expression of the gene, in both adult and fetal human tissues. Transient expression in COS7 cells permitted the detection of a sialidase activity with high activity towards ganglioside substrates at a pH optimum of 3.8. Immunofluorescence staining of the transfected COS7 cells demonstrated the protein's localization in the plasma membrane.

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27

Lillehoj, Erik P., Sang Won Hyun, Chiguang Feng, Lei Zhang, Anguo Liu, Wei Guang, Chinh Nguyen, et al. "Human airway epithelia express catalytically active NEU3 sialidase." American Journal of Physiology-Lung Cellular and Molecular Physiology 306, no. 9 (May 1, 2014): L876—L886. http://dx.doi.org/10.1152/ajplung.00322.2013.

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Sialic acids on glycoconjugates play a pivotal role in many biological processes. In the airways, sialylated glycoproteins and glycolipids are strategically positioned on the plasma membranes of epithelia to regulate receptor-ligand, cell-cell, and host-pathogen interactions at the molecular level. We now demonstrate, for the first time, sialidase activity for ganglioside substrates in human airway epithelia. Of the four known mammalian sialidases, NEU3 has a substrate preference for gangliosides and is expressed at mRNA and protein levels at comparable abundance in epithelia derived from human trachea, bronchi, small airways, and alveoli. In small airway and alveolar epithelia, NEU3 protein was immunolocalized to the plasma membrane, cytosolic, and nuclear subcellular fractions. Small interfering RNA-induced silencing of NEU3 expression diminished sialidase activity for a ganglioside substrate by >70%. NEU3 immunostaining of intact human lung tissue could be localized to the superficial epithelia, including the ciliated brush border, as well as to nuclei. However, NEU3 was reduced in subepithelial tissues. These results indicate that human airway epithelia express catalytically active NEU3 sialidase.

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28

Albrecht, Camille, Zachée Louis Evariste Akissi, Philomène Akoua Yao-Kouassi, Abdulmagid Alabdul Magid, Pascal Maurice, Laurent Duca, Laurence Voutquenne-Nazabadioko, and Amar Bennasroune. "Identification and Evaluation of New Potential Inhibitors of Human Neuraminidase 1 Extracted from Olyra latifolia L.: A Preliminary Study." Biomedicines 9, no. 4 (April 11, 2021): 411. http://dx.doi.org/10.3390/biomedicines9040411.

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Sialidases, also called neuraminidases, are involved in several human pathologies such as neurodegenerative disorders, cancers, as well as infectious and cardiovascular diseases. Several studies have shown that neuraminidases, such as neuraminidase 1 (NEU-1), may be promising pharmacological targets. Therefore, the discovery of new selective inhibitors of NEU-1 are necessary to better understand the biological functions of this sialidase. In the present study, we describe the isolation and characterization of nine known compounds from Olyra latifolia L. leaves. This plant, known to have several therapeutic properties, belongs to the family of Poaceae and is found in the neotropics and in tropical Africa and Madagascar. Among the purified compounds, feddeiketone B, 2,3-dihydroxy-1-(4-hydroxy-3,5-diméthoxyphényl)-l-propanone, and syringylglycerol were shown to present structural analogy with DANA, and their effects on membrane NEU-1 sialidase activity were evaluated. Our results show that they possess inhibitory effects against NEU-1-mediated sialidase activity at the plasma membrane. In conclusion, we identified new natural bioactive molecules extracted from Olyra latifolia as inhibitors of human NEU-1 of strong interest to elucidate the biological functions of this sialidase and to target this protein involved in several pathophysiological contexts.

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Zanchetti, Gabriele, Paolo Colombi, Marta Manzoni, Luigi Anastasia, Luigi Caimi, Giuseppe Borsani, Bruno Venerando, et al. "Sialidase NEU3 is a peripheral membrane protein localized on the cell surface and in endosomal structures." Biochemical Journal 408, no. 2 (November 14, 2007): 211–19. http://dx.doi.org/10.1042/bj20070503.

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Sialidase NEU3 is also known as the plasma-membrane-associated form of mammalian sialidases, exhibiting a high substrate specificity towards gangliosides. In this respect, sialidase NEU3 modulates cell-surface biological events and plays a pivotal role in different cellular processes, including cell adhesion, recognition and differentiation. At the moment, no detailed studies concerning the subcellular localization of NEU3 are available, and the mechanism of its association with cellular membranes is still unknown. In the present study, we have demonstrated that sialidase NEU3, besides its localization at the plasma membrane, is present in intracellular structures at least partially represented by a subset of the endosomal compartment. Moreover, we have shown that NEU3 present at the plasma membrane is internalized and locates then to the recycling endosomal compartment. The enzyme is associated with the outer leaflet of the plasma membrane, as shown by selective cell-surface protein biotinylation. This evidence is in agreement with the ability of NEU3 to degrade gangliosides inserted into the plasma membrane of adjacent cells. Moreover, the mechanism of the protein association with the lipid bilayer was elucidated by carbonate extraction. Under these experimental conditions, we have succeeded in solubilizing NEU3, thus demonstrating that the enzyme is a peripheral membrane protein. In addition, Triton X-114 phase separation demonstrates further the hydrophilic nature of the protein. Overall, these results provide important information about the biology of NEU3, the most studied member of the mammalian sialidase family.

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Pshezhetsky, Alexey, Volkan Seyrantepe, Lionel Carmant, Thierry Levade, Roy Gravel, Jacques Michaud, and Carlos Morales. "110. Mice double-deficient in lysosomal hexosaminidase A and sialidase Neu4 show epileptic crises accompanied by rapid loss of cortical and hippocampal neurons." Molecular Genetics and Metabolism 96, no. 2 (February 2009): S36. http://dx.doi.org/10.1016/j.ymgme.2008.11.111.

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31

WANG, Peng, Ji ZHANG, Hong BIAN, Ping WU, Reshma KUVELKAR, Ted T. KUNG, Yvette CRAWLEY, Robert W. EGAN, and M. Motasim BILLAH. "Induction of lysosomal and plasma membrane-bound sialidases in human T-cells via T-cell receptor." Biochemical Journal 380, no. 2 (June 1, 2004): 425–33. http://dx.doi.org/10.1042/bj20031896.

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Among the three isoenzymes of neuraminidase (Neu) or sialidase, Neu-1 has been suggested to be induced by cell activation and to be involved in IL (interleukin)-4 biosynthesis in murine T-cells. In the present study, we found that antigen-induced airway eosinophilia, a typical response dependent on Th2 (T-helper cell type 2) cytokines, as well as mRNA expression of Th2 cytokines, including IL-4, are suppressed in Neu-1-deficient mice, thereby demonstrating the in vivo role of murine Neu-1 in regulation of Th2 cytokines. To elucidate the roles of various sialidases in human T-cell activation, we investigated their tissue distribution, gene induction and function. Neu-1 is the predominant isoenzyme at the mRNA level in most tissues and cells in both mice and humans, including T-cells. T-cells also have significant levels of Neu-3 mRNAs, albeit much lower than those of Neu-1, whereas the levels of Neu-2 mRNAs are minimal. In human T-cells, both Neu-1 and Neu-3 mRNAs are significantly induced by T-cell-receptor stimulation, as is sialidase activity against 4-methylumbelliferyl-N-acetylneuramic acid (a substrate for both Neu-1 and Neu-3) and the ganglioside GD1a [NeuAcα2-3Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glcβ1-cer] (a substrate for Neu-3, but not for Neu-1). The expression of the two sialidase genes may be under differential regulation. Western blot analysis and enzymic comparison with recombinant sialidases have revealed that Neu-3 is induced as a major isoform in activated cells. The induction of Neu-1 and Neu-3 in T-cells is unique. In human monocytes and neutrophils stimulated with various agents, the only observation of sialidase induction has been by IL-1 in neutrophils. Functionally, a major difference has been observed in Jurkat T-cell lines over-expressing Neu-1- and Neu-3. Upon T-cell receptor stimulation, IL-2, interferon-γ, IL-4 and IL-13 are induced in the Neu-1 line, whereas in the Neu-3 line the same cytokines are induced, with the exception of IL-4. Taken together, these results suggest an important immunoregulatory role for both Neu-1 and Neu-3 in humans.

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Grozovsky, Renata, Gerard Jansen, and Karin M. Hoffmeister. "Sialic Acid Loss Regulates Platelet Survival and Integrity." Blood 122, no. 21 (November 15, 2013): 3504. http://dx.doi.org/10.1182/blood.v122.21.3504.3504.

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Abstract It becomes increasingly apparent that, besides the intrinsic apoptotic machinery, surface glycan modifications regulate platelet survival. Platelets with reduced α2,3-linked sialic acid during sepsis due to S. pneumoniae infection, after cold storage, or in mice lacking the sialyltransferase ST3GalIV are cleared by the hepatic Ashwell-Morell receptor (AMR, ASGPR1/2). Platelet survival in Asgr2-/- mice was increased by ∼35% when compared to that of WT mice, which results in a ∼50% increase in circulating platelet counts, despite a loss of surface sialic acid. We reasoned that sialidase activity increases on the surface of circulating platelets as they age, a process that would facilitate sialic acid hydrolysis and removal from the circulation. To test this hypothesis, we directly injected the sialidase inhibitor 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA) into WT mice and determined endogenous platelet circulatory times. Platelet survival was prolonged by ∼30% (T1/2 of 62.0 ± 2.7 h) in DANA-treated mice, compared to that of mock-treated mice (T1/2 of 47.5 ± 4.3 h). DANA injections decreased terminal sialic acid loss on circulating platelets by ∼40% by day 2, compared to control platelets, as evidenced by binding of RCA-I lectin that specifically recognizes terminal β1-4 galactose moieties exposed by sialic acid removal. Freshly isolated, resting platelets from Asgr2-/- mice (AMR-platelets) were significantly smaller in size (22%) and had increased sialidase Neu1 (∼5 fold), but not Neu3 surface expression, when compared to WT platelets or St3gal4-/- platelets, as measured by flow cytometry. We next investigated if AMR-platelets age/deteriorate faster upon in vitro storage. Platelets were isolated from WT, Asgr2-/- and St3gal4-/- mice and stored for 24hrs at room temperature, and sialidase expression (Neu1 and Neu3) as well as microvesiculation were measured by flow cytometry. Although significant Neu1 and Neu3 surface expression increase was measured on platelets from all phenotype after storage, Neu1 and Neu3 surface expression was significantly higher in AMR-platelets (∼2 and 4 fold, respectively) when compared to WT and St3gal4-/- platelets. AMR-platelets, but not St3gal4-/- platelets microvesiculated upon storage, consistent with a faster deterioration of aged AMR-platelets. We next injected into WT and Asgr2-/- mice the BH3 mimetic, ABT-737, which binds and inhibits the pro-apoptotic Bcl-2, Bcl-xL and Bcl-w. After injection of ABT-737, platelets in the Asgr2-/- mouse were cleared more efficiently (∼20%) from the circulation when compared to those in WT mice. Collectively, our data show that blood borne sialidases contribute to loss of sialic acid during circulation to regulate platelet survival. Our data also suggest that platelet glycan degradation, i.e. sialic acid loss, may trigger the intrinsic apoptotic machinery in platelets, linking glycan degradation and intrinsic apoptotic machinery in the clearance mechanisms regulating platelet survival. Disclosures: No relevant conflicts of interest to declare.

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Peng, Li, Lizhi Cao, Sujata Nerle, Robert LeBlanc, Abhishek Das, Sandip Shelke, Autumn Turner, et al. "843 Development and engineering of human sialidase for degradation of immunosuppressive sialoglycans to treat cancer." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A884. http://dx.doi.org/10.1136/jitc-2021-sitc2021.843.

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BackgroundSialoglycans, a type of glycans with a terminal sialic acid, have emerged as a critical glyco-immune checkpoint that impairs antitumor response by inhibiting innate and adaptive immunity. Upregulation of sialoglycans on tumors has been observed for decades and correlates with poor clinical outcomes across many tumor types. We previously showed that targeted desialylation of tumors using a bifunctional sialidase x antibody molecule, consisting of sialidase and a tumor-associated antigen (TAA)-targeting antibody, has led to robust single-agent efficacy in mouse tumor models. In addition to tumor cells, most immune cells present substantially more abundant sialoglycans than non-hematological healthy cells, which may also contribute to immunosuppression. Therefore, we studied the impact of immune cell desialylation and evaluated the therapeutic potential of a newly developed sialidase-Fc fusion (Bi-Sialidase), which lacks a TAA-targeting moiety and consists of engineered human neuraminidase 2 (Neu2) and human IgG1 Fc region, in preclinical mouse tumor models.MethodsThe first generation Neu2 variant was further optimized to improve titers and stability to constructed Bi-Sialidase. Bi-Sialidase’s desialylation potency and impact on immune responses were studied in vitro using various human immune functional assays, including T-cell activation, allogeneic mixed lymphocyte reaction, antibody-dependent cellular cytotoxicity, macrophages polarization/activation, neutrophil activation, and peripheral blood mononuclear cell (PBMC) cytokine release assays. We evaluated its antitumor efficacy in mouse tumor models. Bi-Sialidase’s safety profile was characterized by conducting rat and non-human primate (NHP) toxicology studies.ResultsThe optimized Bi-Sialidase achieved a titer of 2.5 g/L from a 15-day fed-batch Chinese hamster ovary cell culture; in contrast, the wild-type and first-generation Neu2 had no production or a low titer (<0.1 g/L) under similar conditions, respectively. We demonstrated that Bi-Sialidase led to dose-dependent desialylation of immune cells and potentiated T-cell immunity, without impacting NK, macrophage, or neutrophil activation by desialylating immune cells. Activated and exhausted T cells upregulated surface sialoglycans and Bi-Sialidase-mediated desialylation reinvigorated exhausted-like T cells as measured by IFNg production. Bi-Sialidase treatment also enhanced DC priming and activation of naïve T cells by desialylating both T cells and DCs. Furthermore, Bi-Sialidase showed single-agent antitumor activity in multiple mouse tumor models, including MC38, CT26, A20, and B16F10. Importantly, Bi-Sialidase did not cause cytokine release in human PBMC assays and was tolerated to up to 100 mg/kg in rats and NHPs, demonstrating a wide safety margin.ConclusionsBi-Sialidase with an optimized Neu2 offers a novel immunomodulatory approach to enhancing T-cell immunity by desialylating immunosuppressive sialoglycans for cancer treatment.

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Jansen, Gerard, Emma C. Josefsson, Qiyong Peter Liu, Viktoria Rumjantseva, Herve Falet, Renata Grozovsky, Wolfgang Bergmeier, Denisa D. Wagner, John H. Hartwig, and Karin M. Hoffmeister. "Inhibition of Sialic Acid Loss Greatly Improves Survival of Refrigerated Platelets." Blood 118, no. 21 (November 18, 2011): 1133. http://dx.doi.org/10.1182/blood.v118.21.1133.1133.

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Abstract Abstract 1133 Platelets have the shortest shelf life of all major blood components and are the most difficult to store, a fact that complicates platelet transfusion practices. Platelet refrigeration could slow bacterial growth and possibly retard the loss of platelet function following storage. However, in contrast to other blood components, platelets do not tolerate refrigeration and are rapidly cleared from the circulation. We demonstrated that two distinct pathways recognizing GPIba remove refrigerated platelets in recipient's livers: 1) αMβ2 integrins (Mac-1) on hepatic resident macrophages (Kupffer cells) selectively recognize irreversibly clustered b-N-acetylglucosamine (β-GlcNAc)–terminated glycans on GPIbα, and 2) hepatic Asialoglycoprotein (Asg) receptors (Ashwell Morell receptors) recognize desialylated GPIba. We here investigated the mechanism of sialic acid loss during refrigeration. We show, that when refrigerated platelets are rewarmed, they secrete active sialidases, including the lysosomal sialidase Neu1 that remove sialic acid from platelet receptors, specifically from GPIbα. Platelets also express Neu3 on their surfaces, however Neu3 expression appears to be unaffected by platelet refrigeration. Importantly, the recovery and circulation of refrigerated platelets is greatly improved by storage in the presence of the competitive sialidase inhibitor N-Acetylneuraminic Acid, 2,3-Dehydro-2-deoxy-Sodium Salt (DANA). Desialylated von Willebrand receptor (vWfR) complex is also a target for metalloproteinases (MMPs), as GPIbα and GPV are cleaved from the surface of refrigerated platelets. Receptor shedding is inhibited by the metalloproteinase inhibitor GM6001 and does not occur in ADAM17ΔZn/ΔZn platelets expressing inactive ADAM17. Critically, desialylation in the absence of metalloproteinase-mediated receptor shedding is sufficient to induce the rapid clearance of platelets from circulation. Desialylation of platelet vWfR therefore triggers platelet clearance, and primes GPIbα and GPV for metalloproteinase-dependent cleavage. We conclude that desialylation of platelets is caused by increased surface sialidase activity following refrigeration and desialylation of glycoproteins, specifically of GPIbα, promotes receptor cleavage by MMPs. Disclosures: Liu: Velicomedical, Inc: Employment.

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Toussaint, Kévin, Aline Appert-Collin, Hamid Morjani, Camille Albrecht, Hervé Sartelet, Béatrice Romier-Crouzet, Pascal Maurice, Laurent Duca, Sébastien Blaise, and Amar Bennasroune. "Neuraminidase-1: A Sialidase Involved in the Development of Cancers and Metabolic Diseases." Cancers 14, no. 19 (October 5, 2022): 4868. http://dx.doi.org/10.3390/cancers14194868.

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Sialidases or neuraminidases (NEU) are glycosidases which cleave terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Four types of mammalian sialidases, which are encoded by different genes, have been described with distinct substrate specificity and subcellular localization: NEU-1, NEU-2, NEU-3 and NEU-4. Among them, NEU-1 regulates many membrane receptors through desialylation which results in either the activation or inhibition of these receptors. At the plasma membrane, NEU-1 also associates with the elastin-binding protein and the carboxypeptidase protective protein/cathepsin A to form the elastin receptor complex. The activation of NEU-1 is required for elastogenesis and signal transduction through this receptor, and this is responsible for the biological effects that are mediated by the elastin-derived peptides (EDP) on obesity, insulin resistance and non-alcoholic fatty liver diseases. Furthermore, NEU-1 expression is upregulated in hepatocellular cancer at the mRNA and protein levels in patients, and this sialidase regulates the hepatocellular cancer cells’ proliferation and migration. The implication of NEU-1 in other cancer types has also been shown notably in the development of pancreatic carcinoma and breast cancer. Altogether, these data indicate that NEU-1 plays a key role not only in metabolic disorders, but also in the development of several cancers which make NEU-1 a pharmacological target of high potential in these physiopathological contexts.

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Finlay, Trisha M., Preethi Jayanth, Schammim Ray Amith, Alanna Gilmour, Christina Guzzo, Katrina Gee, Rudi Beyaert, and Myron R. Szewczuk. "Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9." Glycoconjugate Journal 27, no. 3 (March 6, 2010): 329–48. http://dx.doi.org/10.1007/s10719-010-9281-6.

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D'Avila, Francesca, Cristina Tringali, Nadia Papini, Luigi Anastasia, Gianluigi Croci, Luca Massaccesi, Eugenio Monti, Guido Tettamanti, and Bruno Venerando. "Identification of lysosomal sialidase NEU1 and plasma membrane sialidase NEU3 in human erythrocytes." Journal of Cellular Biochemistry 114, no. 1 (November 14, 2012): 204–11. http://dx.doi.org/10.1002/jcb.24355.

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Grozovsky, Renata, Qiyong Peter Liu, Andrew Hanneman, David J. Ashline, Hailong Zhang, Vernon Reinhold, and Karin M. Hoffmeister. "The Human Platelet Glycome and Its Variations Among Healthy Volunteers and Storage." Blood 122, no. 21 (November 15, 2013): 2300. http://dx.doi.org/10.1182/blood.v122.21.2300.2300.

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Abstract Platelets have the shortest shelf-life of all major blood components and are the most difficult to store complicating platelet transfusion practices. Transfused fresh radiolabeled autologous platelets differ significantly in recovery and survival among healthy subjects, however the cause of the inter-individual differences remains unclear. We demonstrated that the loss of sialic acid from the surfaces of cold-stored and transfused platelets promotes their clearance by Ashwell Morell receptors. The loss of platelet surface sialic acid correlates with increases in surface sialidase activity during platelet storage. Here we investigated whether fresh platelets from individual donors exhibit differences in surface sialidase expression and glycan exposure and sialic acid content changes with storage. Methods Platelets were isolated by standard methods from the venous blood of healthy volunteers or from standard platelet concentrates (PCs) and analyzed by flow cytometry for surface β-galactose using FITC-conjugated E. cristagalli lectin (ECL). Platelet surface sialidase expression was measured by flow cytometry using antibodies to sialidases Neu1 and Neu3. Sialidase activities were assayed using standard methods, Platelet uptake by hepatocytes was measured by using the human hepatoma cell line HepG2. To further elucidate these issues in a structural biology context we performed baseline study of the N- and O-linked glycans and glycosphingolipids (GSLs) in platelets, and any structural changes observed during storage, by employing HPLC, LC-MS/(MS), and sequential mass spectrometry (MSn) approaches. Results We found that terminal galactose on freshly-isolated platelet glycoproteins varies considerably among healthy subjects: Seven of ten individuals had low levels of exposed galactose (15.3 ± 4.1, MFI) and three subjects exhibited significantly higher levels of terminal galactose as detected by flow cytometry using lectins. Reduced sialic acid content correlated with increased surface sialidase activity and expression. Platelets with high terminal galactose were ingested with a higher rate by HepG2 cells, i.e via Ashwell Morell receptors. Importantly, individuals with low sialic acid levels correlate with low platelet counts at steady state. Structural analysis revlealed that fresh platelet N-glycan pools include a significant amount of high-mannose (Man5-Man9) and asialo complex glycans, however, are dominated by a diverse range of complex sialylated structures with two to four antennae, up to four NeuAcs, and include antennary fucosylation, and five or more lactosamine extensions. The O-linked fractions are comprised of core-1 and core-2 glycans having zero, one, or two NeuAc residues. A significant decrease in sialylation during conventional platelet storage at room temperature was confirmed at the level of individual O-glycan structures. Quantitative analysis of the more structurally complex N-glycan pools is ongoing. Conclusion Our results show that fresh platelets from healthy individuals vary in surface sialidase activity and sialic acid content and exhibit a high complexity in glycan structures. Collectively we propose that individual platelet counts may be dependent on surface sialic acid content and that the surface sialic acid could represent a factor that affects the recovery and survival of transfused platelets. Disclosures: No relevant conflicts of interest to declare.

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Chen, X. P., E. Y. Enioutina, and R. A. Daynes. "The control of IL-4 gene expression in activated murine T lymphocytes: a novel role for neu-1 sialidase." Journal of Immunology 158, no. 7 (April 1, 1997): 3070–80. http://dx.doi.org/10.4049/jimmunol.158.7.3070.

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Abstract IL-4 is important in controlling the development of immune responses. Following activation with anti-CD3epsilon under serum-free conditions, splenocytes from most normal (neu-1b) mouse strains directly produced IL-4 and other T cell cytokines. However, splenic T cells from SM/J and B10.SM (H-2v, neu-1a) strain mice, deficient in neu-1 sialidase activity, failed to produce IL-4 but produced normal levels of IL-2 following activation. Moreover, sialidase-deficient mice produced markedly less IgE and IgG1 Abs following immunization with protein Ags than did mouse strains with normal neu-1 sialidase activity. Enriched T cells from neu-1a mice failed to be effectively primed with exogenous murine IL-4 to become IL-4-producing cells. Treatment of splenocytes or enriched T cells from neu-1a mice with bacterial sialidase prior to activation or IL-4 priming promoted their subsequent capacity to produce IL-4. In contrast, activation of T cells from neu-1b mice in the presence of a sialidase inhibitor almost completely blocked subsequent IL-4 production. The presence of IL-4 during priming enhanced T cell expression of neu-1-specific sialidase activity and increased the membrane expression of asialo-G(M1) compared with T cells activated without IL-4. These results suggest that T cell-associated neu-1 sialidase is required for early IL-4 production by splenic T cells and is involved in the IL-4 priming process of conventional T cells to become active IL-4 producers.

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Karhadkar, Tejas R., Wensheng Chen, and Richard H. Gomer. "Attenuated pulmonary fibrosis in sialidase-3 knockout (Neu3−/−) mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 1 (January 1, 2020): L165—L179. http://dx.doi.org/10.1152/ajplung.00275.2019.

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Pulmonary fibrosis involves the formation of inappropriate scar tissue in the lungs, but what drives fibrosis is unclear. Sialidases (also called neuraminidases) cleave terminal sialic acids from glycoconjugates. In humans and mice, pulmonary fibrosis is associated with desialylation of glycoconjugates and upregulation of sialidases. Of the four mammalian sialidases, we previously detected only NEU3 in the bronchoalveolar lavage fluid from mice with bleomycin-induced pulmonary fibrosis. In this report, we show that NEU3 upregulates extracellular accumulation of the profibrotic cytokines IL-6 and IL-1β, and IL-6 upregulates NEU3 in human peripheral blood mononuclear cells, suggesting that NEU3 may be part of a positive feedback loop potentiating fibrosis. To further elucidate the role of NEU3 in fibrosis, we used bleomycin to induce lung fibrosis in wild-type C57BL/6 and Neu3−/− mice. At 21 days after bleomycin, compared with male and female C57BL/6 mice, male and female Neu3−/− mice had significantly less inflammation, less upregulation of other sialidases and the profibrotic cytokine active transforming growth factor β1, and less fibrosis in the lungs. Our results suggest that NEU3 participates in fibrosis and that NEU3 could be a target to develop treatments for fibrosis.

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Rodriguez-Walker, Macarena, Aldo A. Vilcaes, Eduardo Garbarino-Pico, and José L. Daniotti. "Role of plasma-membrane-bound sialidase NEU3 in clathrin-mediated endocytosis." Biochemical Journal 470, no. 1 (August 6, 2015): 131–44. http://dx.doi.org/10.1042/bj20141550.

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Sialidase NEU3 is a key enzyme in the catabolism of gangliosides. We demonstrated that NEU3 impairs cargo internalization via clathrin-coated pits, affecting AP-2 subcellular distribution. This study delineates previously unidentified cellular functions of NEU3.

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Cross, Alan S., Sang Won Hyun, Alba Miranda-Ribera, Chiguang Feng, Anguo Liu, Chinh Nguyen, Lei Zhang, et al. "NEU1 and NEU3 Sialidase Activity Expressed in Human Lung Microvascular Endothelia." Journal of Biological Chemistry 287, no. 19 (March 8, 2012): 15966–80. http://dx.doi.org/10.1074/jbc.m112.346817.

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Akyildiz Demir, Secil, and Volkan Seyrantepe. "Identification of cytoplasmic sialidase NEU2-associated proteins by LC-MS/MS." Turkish Journal of Biochemistry 44, no. 4 (August 3, 2018): 462–72. http://dx.doi.org/10.1515/tjb-2018-0089.

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Abstract Background Cytoplasmic sialidase (NEU2) plays an active role in removing sialic acids from oligosaccharides, glycopeptides, and gangliosides in mammalian cells. NEU2 is involved in various cellular events, including cancer metabolism, neuronal and myoblast differentiation, proliferation, and hypertrophy. However, NEU2-interacting protein(s) within the cell have not been identified yet. Objective The aim of this study is to investigate NEU2 interacting proteins using two-step affinity purification (TAP) strategy combined with mass spectrometry analysis. Methods In this study, NEU2 gene was cloned into the pCTAP expression vector and transiently transfected to COS-7 cells by using PEI. The most efficient expression time of NEU2- tag protein was determined by real-time PCR and Western blot analysis. NEU2-interacting protein(s) were investigated by using TAP strategy combined with two different mass spectrometry experiment; LC-MS/MS and MALDI TOF/TOF. Results Here, mass spectrometry analysis showed four proteins; α-actin, β-actin, calmodulin and histone H1.2 proteins are associated with NEU2. The interactions between NEU2 and actin filaments were verified by Western blot analysis and immunofluorescence analysis. Conclusions Our study suggests that association of NEU2 with actin filaments and other protein(s) could be important for understanding the biological role of NEU2 in mammalian cells.

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Wang, Qian-ming, Xiao-Hui Zhang, Fei-er Feng, Chen-cong Wang, Wei Han, Huan Chen, Lan-ping Xu, and Xiao Jun Huang. "Desialylation Induces Apoptosis and Phagocytosis of Platelets in Patients with Prolonged Isolated Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 432. http://dx.doi.org/10.1182/blood.v124.21.432.432.

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Abstract Introduction: Prolonged isolated thrombocytopenia (PIT) represents a significant complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and is associated with an adverse patient prognosis and higher transplant-related mortality owing to a higher risk of infection events, severe (grades 3 to 4) acute graft-versus-host disease (GVHD) and chronic GVHD. PIT is defined as a peripheral platelet count less than 100×109/L without sustained anemia or leukopenia for more than 3 months after allo-HSCT (Zhang X, et al. Biol Blood Marrow Transplant, 2011). However, the underlying mechanisms remain unclear. Different kinds of functional glycoproteins are expressed on the platelet surface, with sialic acid residues at the end of their glycan. Desialylation of platelet glycoproteins has been found to be associated with accelerated platelet clearance in refrigerated platelets (Gerard Jansen AJ, et al. Blood 2012). Platelet-specific glycoprotein GPIbα,the functional subunit of the von Willebrand factor receptor, was the majorly desialylated glycoprotein; NEU1, one of the four human sialidases, was the enzyme that catalyzed GPIbα desialylation. However, few studies have focused on this mechanism in patients suffering PIT after allo-HSCT. In this study, we hypothesized that desialylation on platelet surfaces is associated with PIT after allo-HSCT. The mechanisms participating in this process may include GPIbα clustering, platelet apoptosis and phagocytosis by macrophages. Patients and methods: Blood samples were collected 90 days after allo-HSCT from 70 patients with PIT. Samples from post-transplantation patients who have normal platelet counts were taken as controls. Sialylation and desialylation were measured by detecting specific lectins via flow cytometry. Human sialidase expression was determined by immunofluorescence, flow cytometry and reverse transcription PCR. Platelet apoptosis markers were measured by flow cytometry, and macrophages stimulated from THP-1 cells were used in the phagocytosis assay. Results: We tested sialic acid residues and the desialylation markers, including β-galactose and β-N-Acetyl glucosamine, on the platelet surface, and found that platelets from PIT patients had significantly higher desialylation levels. Serum sialic acid levels were measured, and the results showed higher levels in PIT patients. Further, NEU1 was found to be over-expressed on the surface of platelets from PIT patients, and was found to be the enzyme that catalyzed the platelet surface desialylation. To further reveal the mechanism that lead to PIT, we proved that GPIbα was the desialylated glycoprotein on platelets from PIT patients. We found that GPIbα desialylation and clustering in PIT patients induced changes in the expression of Bcl-2 family protein, as a 2-fold increase in active Bax expression and a similar decrease in Bcl-XL expression were observed. Depolarization of the inner mitochondria membrane was augmented in desialylated platelets from PIT patients, indicating increased platelet apoptosis. Moreover, macrophages stimulated from the THP-1 cell line preferred to phagocytose desialylated platelets from PIT patients in vitro; this process could be blocked by the sialidase inhibitor, DANA. In the in vitrostudy, we found that dexamethasone led to a 32% decrease in phagocytosis, whereas oseltamivir, an antiviral medicine that can block sialidase from influenza virus, could also partially function on human sialidase and protect 43% of platelets from phagocytosis. In conclusion, our results demonstrate that desialylation played a role in the mechanism of prolonged isolated thrombocytopenia after allo-HSCT, most likely through platelet apoptosis induction and increased phagocytosis by macrophages in the peripheral circulation. Dexamethasone and oseltamivir could decrease platelet apoptosis and inhibit platelet phagocytosis in vitro, implying a novel potential method for treating PIT after allo-HSCT. Disclosures No relevant conflicts of interest to declare.

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Che, Jenny, Lihui Xu, Wayne Gatlin, Robert LeBlanc, Lizhi Cao, James Broderick, and Li Peng. "Abstract LB221: Development of PD-L1-targeted sialidase as a novel cancer immunotherapeutic approach." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB221. http://dx.doi.org/10.1158/1538-7445.am2022-lb221.

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Abstract Sialoglycans have emerged as a critical glyco-immune checkpoint that impairs antitumor response by inhibiting innate and adaptive immunity. We have previously reported that Bi-Sialidase - an engineered human sialidase-Fc fusion - potentiates antitumor immune response by cleaving terminal sialic acids from sialoglycans (desialylating) on tumor cells and immune cells. Furthermore, we have shown that a tumor-targeted sialidase, a heterodimeric molecule consisting of one chain of sialidase-Fc and a second chain of a HER2-targeting antibody (trastuzumab), leads to more efficient desialylation of tumor cells than the non-targeted Bi-Sialidase and demonstrates antitumor activity in trastuzumab-resistant and low HER2-expressing tumor models. To evaluate the potential of targeted desialylation of both tumor cells and immune cells, we designed and characterized a PD-L1-targeted sialidase in preclinical models, since PD-L1 is expressed on both tumor cells and immune cells. Furthermore, the design of the PD-L1-targeted sialidase enables the combinatorial blockade of two orthogonal immune checkpoint pathways, inhibiting both the PD-1/PD-L1 axis and immunosuppressive sialoglycans. We generated a humanized anti-human PD-L1 antibody with comparable PD-1/PD-L1 blockade potency to the existing anti-PD-L1 drugs, atezolizumab and avelumab. Subsequently, we constructed a bifunctional heterodimeric molecule, consisting of one chain of sialidase-Fc of a third generation of engineered human sialidase (Neu 2) and a second chain of the in-house generated anti-PD-L1 antibody. The PD-L1-targeted sialidase maintained its potency for inhibiting the PD-1/PD-L1 axis as compared to its parental anti-PD-L1 antibody, and demonstrated improved desialylation of PD-L1-expressing tumor cells and immune cells in vitro. We tested the PD-L1-targeted sialidase in transgenic mouse tumor models that express human PD-1 and PD-L1 replacing their murine counterparts, since the parental PD-L1 antibody doesn’t cross-react with the mouse antigen. In the transgenic human PD-L1-expressing mouse colon carcinoma CT26 subcutaneous tumor model, the PD-L1-targeted sialidase exhibited enhanced efficacy compared to the Bi-Sialidase or the anti-PD-L1 antibody. Furthermore, the PD-L1-targeted sialidase demonstrated a dose-dependent tumor growth inhibition and modulation of immune cell infiltration. In conclusion, these results suggested that PD-L1-targeted sialidase offers a promising cancer immunotherapeutic approach, which simultaneously inhibits immunosuppressive sialoglycans and the PD-1/PD-L1 axis through targeted delivery of engineered human sialidase to PD-L1-expressing tumor cells and immune cells. Citation Format: Jenny Che, Lihui Xu, Wayne Gatlin, Robert LeBlanc, Lizhi Cao, James Broderick, Li Peng. Development of PD-L1-targeted sialidase as a novel cancer immunotherapeutic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB221.

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Khedri, Zahra, Yanhong Li, Hongzhi Cao, Jingyao Qu, Hai Yu, Musleh M. Muthana, and Xi Chen. "Synthesis of selective inhibitors against V. cholerae sialidase and human cytosolic sialidase NEU2." Organic & Biomolecular Chemistry 10, no. 30 (2012): 6112. http://dx.doi.org/10.1039/c2ob25335f.

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Calhan, O. Y., and V. Seyrantepe. "Mice with Catalytically Inactive Cathepsin A Display Neurobehavioral Alterations." Behavioural Neurology 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/4261873.

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The lysosomal carboxypeptidase A, Cathepsin A (CathA), is a serine protease with two distinct functions. CathA protects β-galactosidase and sialidase Neu1 against proteolytic degradation by forming a multienzyme complex and activates sialidase Neu1. CathA deficiency causes the lysosomal storage disease, galactosialidosis. These patients present with a broad range of clinical phenotypes, including growth retardation, and neurological deterioration along with the accumulation of the vasoactive peptide, endothelin-1, in the brain. Previous in vitro studies have shown that CathA has specific activity against vasoactive peptides and neuropeptides, including endothelin-1 and oxytocin. A mutant mouse with catalytically inactive CathA enzyme (CathAS190A) shows increased levels of endothelin-1. In the present study, we elucidated the involvement of CathA in learning and long-term memory in 3-, 6-, and 12-month-old mice. Hippocampal endothelin-1 and oxytocin accumulated in CathAS190A mice, which showed learning impairments as well as long-term and spatial memory deficits compared with wild-type littermates, suggesting that CathA plays a significant role in learning and in memory consolidation through its regulatory role in vasoactive peptide processing.

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Lorenz, Lea, Barbara Amann, Sieglinde Hirmer, Roxane L. Degroote, Stefanie M. Hauck, and Cornelia A. Deeg. "NEU1 is more abundant in uveitic retina with concomitant desialylation of retinal cells." Glycobiology 31, no. 7 (February 23, 2021): 873–83. http://dx.doi.org/10.1093/glycob/cwab014.

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Abstract Desialylation of cell surface glycoproteins carried out by sialidases affects various immunological processes. However, the role of neuraminidase 1 (NEU1), one of the four mammalian sialidases, in inflammation and autoimmune disease is not completely unraveled to date. In this study, we analyzed the retinal expression of NEU1 in equine recurrent uveitis (ERU), a spontaneous animal model for autoimmune uveitis. Mass spectrometry revealed significantly higher abundance of NEU1 in retinal Müller glial cells (RMG) of ERU-diseased horses compared to healthy controls. Immunohistochemistry uncovered NEU1 expression along the whole Müller cell body in healthy and uveitic states and confirmed higher abundance in inflamed retina. Müller glial cells are the principal macroglial cells of the retina and play a crucial role in uveitis pathogenesis. To determine whether higher expression levels of NEU1 in uveitic RMG correlate with the desialylation of retinal cells, we performed lectin-binding assays with sialic acid-specific lectins. Through these experiments, we could demonstrate a profound loss of both α2-3- and α2-6-linked terminal sialic acids in uveitis. Hence, we hypothesize that the higher abundance of NEU1 in uveitic RMG plays an important role in the pathogenesis of uveitis by desialylation of retinal cells. As RMG become activated in the course of uveitis and actively promote inflammation, we propose that NEU1 might represent a novel activation marker for inflammatory RMG. Our data provide novel insights in the expression and implication of NEU1 in inflammation and autoimmune disease.

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Piccoli, Marco, Simona Coviello, Maria Elena Canali, Paola Rota, Paolo La Rocca, Federica Cirillo, Ivana Lavota, et al. "Neu3 Sialidase Activates the RISK Cardioprotective Signaling Pathway during Ischemia and Reperfusion Injury (IRI)." International Journal of Molecular Sciences 23, no. 11 (May 29, 2022): 6090. http://dx.doi.org/10.3390/ijms23116090.

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Coronary reperfusion strategies are life-saving approaches to restore blood flow to cardiac tissue after acute myocardial infarction (AMI). However, the sudden restoration of normal blood flow leads to ischemia and reperfusion injury (IRI), which results in cardiomyoblast death, irreversible tissue degeneration, and heart failure. The molecular mechanism of IRI is not fully understood, and there are no effective cardioprotective strategies to prevent it. In this study, we show that activation of sialidase-3, a glycohydrolytic enzyme that cleaves sialic acid residues from glycoconjugates, is cardioprotective by triggering RISK pro-survival signaling pathways. We found that overexpression of Neu3 significantly increased cardiomyoblast resistance to IRI through activation of HIF-1α and Akt/Erk signaling pathways. This raises the possibility of using Sialidase-3 activation as a cardioprotective reperfusion strategy after myocardial infarction.

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Yamaguchi, Kazunori, Koichi Koseki, Momo Shiozaki, Yukiko Shimada, Tadashi Wada, and Taeko Miyagi. "Regulation of plasma-membrane-associated sialidase NEU3 gene by Sp1/Sp3 transcription factors." Biochemical Journal 430, no. 1 (July 28, 2010): 107–17. http://dx.doi.org/10.1042/bj20100350.

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Abstract:

Gene expression of the human plasma membrane-associated sialidase (NEU3), a key enzyme for ganglioside degradation, is relatively high in brain and is modulated in response to many cellular processes, including neuronal cell differentiation and tumorigenesis. We demonstrated previously that NEU3 is markedly up-regulated in various human cancers and showed that NEU3 transgenic mice developed a diabetic phenotype and were susceptible to azoxymethane-induced aberrant crypt foci in their colon tissues. These results suggest that appropriate control of NEU3 gene expression is required for homoeostasis of cellular functions. To gain insights into regulation mechanisms, we determined the gene structure and assessed transcription factor involvement. Oligo-capping analysis indicated the existence of alternative promoters for the NEU3 gene. Transcription started from two clusters of multiple TSSs (transcription start sites); one cluster is preferentially utilized in brain and another in other tissues and cells. Luciferase reporter assays showed further that the region neighbouring the two clusters has promoter activity in the human cell lines analysed. The promoter lacks TATA, but contains CCAAT and CAAC, elements, whose deletions led to a decrease in promoter activity. Electrophoretic mobility-shift assays and chromatin immunoprecipitation demonstrated binding of transcription factors Sp (specificity protein) 1 and Sp3 to the promoter region. Down-regulation of the factors by siRNAs (short interfering RNAs) increased transcription from brain-type TSSs and decreased transcription from other TSSs, suggesting a role for Sp1 and Sp3 in selection of the TSSs. These results indicate that NEU3 expression is diversely regulated by Sp1/Sp3 transcription factors binding to alternative promoters, which might account for multiple modulation of gene expression.

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Journal articles on the topic 'Sialidase NEU4'

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