Sialidases In Vertebrates: A Family Of Enzymes

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Author's personal copy ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL. 64

SIALIDASES IN VERTEBRATES: A FAMILY OF ENZYMES TAILORED

FOR SEVERAL CELL FUNCTIONS*

BY EUGENIO MONTIa, ERIK BONTENb, ALESSANDRA D’AZZOb, ROBERTO BRESCIANIa,

BRUNO VENERANDOc, GIUSEPPE BORSANIa, ROLAND SCHAUERd and

GUIDO TETTAMANTIe

a

Department of Biomedical Science and Biotechnology, University of Brescia, 25123, Italy Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN, 28105-2794, USA c Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, Segrate, 20090, Italy d Institute of Biochemistry, University of Kiel, Kiel, D-24098, Germany e Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, San Donato Milanese, 20097, Italy b

I. Introduction II. The Lysosomal Sialidase NEU1 1. Background 2. Lysosomal Routing and Formation of the Multienzyme Complex 3. Human NEU1 Deficiency 4. New Functions of NEU1 in Tissue Remodeling and Homeostasis 5. Mouse Model of NEU1 Deficiency and Study of Disease Pathogenesis III. The Cytosolic Sialidase NEU2 1. General Properties of NEU2 2. Crystal Structure of Human Sialidase NEU2 3. Functional Implication of NEU2 IV. The Plasma Membrane-Associated Sialidase NEU3 1. General Properties of NEU3 2. Functional Implication of NEU3 V. The Particulate Sialidase NEU4 1. General Properties of NEU4 2. Functional Implication of NEU4 VI. Sialidases and Cancer VII. Sialidases and Immunity VIII. Further Evidence for Possible Functional Implications of Sialidases IX. In silico Analysis of Sialidase Gene Expression Patterns X. Amino Acid Sequence Variants in Human Sialidases XI. Sialidases in Teleosts

ISBN: 978-0-12-380854-7 DOI: 10.1016/S0065-2318(10)64007-3

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XII. Trans-sialidases: What Distinguishes Them from Sialidases? XIII. Final Remarks References

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ABBREVIATIONS 9-OAcGD3, 9-O-acetylated disialo-ganglioside GD3; ACF, aberrant crypt foci; AKT, serine/theonine-specific protein kinase family; ALL, acute lymphoblastic leukemia; ARIs, axon regeneration inhibitors; ASMC, aortic smooth muscle cells; BCL-2, B-cell leukemia/lymphoma 2 integral membrane protein; BM, bone mar­ row; BMT, bone marrow transplantation; BMEF, bone marrow extracellular fluid; CD, cluster of differentiation; CFU-E, colony-forming unit-erythroid cells; CG, cathepsin G; CHO, Chinese Hamster Ovary (cells); CSER, cell-surface elastin receptor; DRMs, detergent-resistant microdomains; EBP, Elastin-Binding Protein; EBP, human gene encoding the Elastin-Binding Protein; EGF, epidermal growth factor; EGFR, epidermal growth-factor receptor; ELISA, enzyme-linked immuno­ sorbent assay; EMH, extramedullary hematopoiesis; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; EST, Expressed Sequence Tag; β-GAL, human gene encoding the β-galactosidase; β-GAL, β-galactosidase; GEMs, glyco­ sphingolipid-enriched microdomains; GS, galactosialidosis; HeLa, cell line was derived from cervical cancer cells taken from a patient named Henrietta Lacks; HLA, human leukocyte antigen; HPCs, hematopoietic progenitor cells; ICAM-1, Intercellular Adhesion Molecule 1 (also known as cluster of differentiation 54 (CD54)); IFN, interferon; IGF-1R, receptor of insulin-like growth factor-1; IL, interleukin; JNK, protein kinase member of the MAP kinase; LacCer, lacto­ syl-ceramide; LAMP, lysosome-associated membrane protein; Lex, Lewisx anti­ gens; LIMP, lysosome integral membrane protein; M6P, mannose 6-phosphate; MAG, myelin-associated glycoprotein; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated or extracellular signal-regulated protein kinase; MHC, major histocompatibility complex; MMP9, gene encoding the matrix metallopro­ teinase-9; MMP9, matrix metalloproteinase-9; MU, methylumbelliferone; NCAM, neural cell adhesion molecule; NCBI, National Center for Biotechnology Informa­ tion; NE, neutrophil elastase; NEU1, gene encoding the lysosomal sialidase; NEU1, human lysosomal sialidase; Neu1, mouse gene encoding the mouse lysosomal Author contributions: Erik Bonten and Alessandra D’Azzo contributed Section II. Giuseppe Borsani contributed Sections IX–X. Roland Schauer contributed Section XII. The remaining authors, together with Giuseppe Borsani, contributed the other sections.

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sialidase; Neu1, mouse lysosomal sialidase; Neu5Ac, N-acetylneuraminic acid; NGF, nerve growth factor; NMR, nuclear magnetic resonance; nsSNP, non-synon­ ymous single nucleotide polymorphism; PAG, phosphoprotein associated with GEMs; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growthfactor receptor; PI3K, phosphoinositide-3 kinase; PKC, protein kinase C; PLC, phosphoinositide-specific phospholipase C; PMA, phorbol 12-tetradecanoate 13-acetate; PPCA, protective protein/cathepsin A; Rac, subfamily of the Rho family of GTPases; RD, cell line derived from a human rhabdomyosarcoma; RMS, rhabdomyosarcoma; RSV, respiratory syncytial virus; RT-PCR, reverse tran­ scription-polymerase chain reaction; SFK, Src family protein tyrosine kinases; shRNA, short hairpin RNA; sLex, sialyl Lewisx antigens; SNP, single nucleotide polymorphism; TERMs, tetraspanin-enriched microdomains; THP-1, human acute monocytic leukemia cell line; TLR, toll-like receptor; TNF, tumor necrosis factor; TrKA, high-affinity catalytic receptor for nerve growth factor; TS, trans-sialidase; Tsk, tight-skin (mouse); VCAM, vascular cell adhesion molecule; VSMC, vascular smooth muscle cells. NOTE Gene and protein symbols are reported according to: H. M. Wain, E. A. Bruford, R. C. Lovering, M. J. Lush, M. W. Wright, and S. Povey, Guidelines for human gene nomenclature, Genomics 79 (2002) 464–470; Refer Guidelines for Nomenclature of Genes, Genetic Markers, Alleles, and Muta­ tions in Mouse and Rat at the Mouse Genome Informatics (MGI) website (http://www. informatics.jax.org/mgihome/nomen/gene.shtml); and Zebrafish Nomenclature Guidelines at the ZFIN website (http://zfin.org/zf_info/nomen.html). Ganglioside nomenclature is according to: L. Svennerholm, Ganglioside designation, Adv. Exp. Med. Biol. 125 (1980) 11.

I. INTRODUCTION Sialidases or neuraminidases (EC 3.2.1.18; N-acylneuraminyl glycohydrolases) are a family of exo-glycosidases that catalyze the hydrolytic cleavage of non-reducing sialic acid residues1 ketosidically linked to the saccharide chains of glycoproteins and glycolipids (gangliosides) as well as to oligo- and poly-saccharides. They are widely distributed in nature, from viruses and microorganisms (such as bacteria, protozoa, and fungi) to vertebrates, but are absent in plants, insects, and yeast.2 The molecular

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cloning of several mammalian sialidases since 1993 and the great development that followed early afterward has been summarized in two reviews.3,4 In vertebrates, mammalian sialidases and their target substrates have been impli­ cated in crucial biological processes, including the regulation of cell proliferation/­ differentiation, clearance of plasma proteins, control of cell adhesion, metabolism of gangliosides and glycoproteins, immunocyte function, modification of receptors, and the developmental modeling of myelin. The pivotal and diverse functions of these enzymes, many of which have not yet been discovered, probably account for the existence of four mammalian sialidases, encoded by different genes and defined as lysosomal (NEU1), cytosolic (NEU2), plasma-membrane (NEU3), and mitochondrial/­ lysosomal/-intracellular membranes (NEU4). These enzymes differ in their subcellular localizations, pH optima, kinetic properties, responses to ions and detergents, and substrate specificities. There appears to be little overlap in function of the individual sialidases, even though they share a common mechanism of action. Here we survey the data published since 2002 on vertebrate (mainly mammalian) sialidase biology. The subject is organized as follows: (i) a description of the four different sialidase forms and their functional implication; (ii) an introductory section on some in silico analysis of the sialidase gene family; (iii) a description of recent findings in lower vertebrates (teleosts); and (iv) a comparison between vertebrate sialidases and trans-sialidases, a peculiar group of sialidases that are able to catalyze the transfer of sialic acid from a donor to an acceptor substrate. These enzymes are present in specific microorganisms, and have been implicated in some mammalian infectious diseases. Finally, based on recent discoveries, we attempt to provide a comprehensive picture of the increasing complexity of the biological roles performed by this enzyme family.

II. THE LYSOSOMAL SIALIDASE NEU1 1. Background Lysosomal sialidase (NEU1) initiates the hydrolysis of sialyl-glycoconjugates by removing their terminal sialic acid residues. The enzyme is present in almost all vertebrate tissues and cell types, and functions in a multienzyme complex containing at least two other hydrolases: the glycosidase β-galactosidase (β-GAL) and the serine carboxypeptidase protective protein/cathepsin A (PPCA). Both the human and murine neuraminidase genes (NEU1 and Neu1) map within the major histocompatibility locus. The corresponding proteins share primary structure characteristics with other mammalian and microbial sialidases. However, unlike other members of this family,

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NEU1 reaches the lysosome and becomes catalytically active by interacting with the auxiliary protein PPCA. NEU1 is also the only sialidase that is linked to two neurodegenerative disorders of glycoprotein metabolism: sialidosis, caused by struc­ tural lesions in the NEU1 gene, and galactosialidosis (GS), a combined deficiency of NEU1 and β-GAL that is secondary to the absence of functional PPCA. Currently, there is no effective therapy for these disorders. The cloning of the cDNAs and genes for both human and mouse NEU1 and the generation of a mouse model for sialidosis have enabled studies of disease pathogenesis as well as the implementation of therapeutic modalities that could eventually become clinically useful. Here we sum­ marize the latest findings on this pivotal enzyme that have uncovered new functions of NEU1 in tissue homeostasis. a. Primary Structure of NEU1.—The human NEU1 gene is localized within the HLA histocompatibility locus on chromosome band 6p21.3, while the murine gene maps to the H-2 locus on chromosome 17, a genomic region syntenic to the human chromosome 6p region.5–8 Both genes have similar genomic organization. The human 1.9 kb NEU1 mRNA encodes a single-chain polypeptide of 415 amino acids that shares 90% sequence identity with murine NEU1 and is highly conserved in other mammalian species. Nevertheless, NEU1 shows higher sequence identity to bacterial sialidases (such as enzymes from Salmonella typhimurium, and Micromonospora viridifaciens, Vibrio cholerae) than to the NEU2, NEU3, and NEU4 polypeptides. The latter three enzymes are in fact more similar to each other (42–44%) than to NEU1 (