Monocyte Differentiation Up-regulates the Expression of the Lysosomal Sialidase, Neu1, and Triggers Its Targeting to the Plasma Membrane via Major Histocompatibility Complex Class II-positive Compartments

Human sialidase (neuraminidase) Neu1 catalyzes lysosomal catabolism of sialylated glycoconjugates. Here we show that during the differentiation of monocytes and the monocytic cell line, THP-1, into macrophages, the majority of Neu1 relocalizes from the lysosomes to the cell surface. In contrast to other cellular sialidases Neu2, Neu3, and Neu4, whose expression either remains unchanged or is down-regulated, Neu1 mRNA, protein and activity are specifically increased during the phorbol 12-myristate 13-acetate-induced differentiation, consistent with a significant induction of the transcriptional activity of the Neu1 gene promoter. The lysosomal carboxypeptidase, cathepsin A, which forms a complex with and activates Neu1 in the lysosome, is sorted to the plasma membrane of the differentiating cells similarly to Neu1. Both proteins are first targeted to the lysosome and then are sorted to the LAMP-2-negative, major histo-compatibility complex II-positive vesicles, which later merge with the plasma membrane. Similar trafficking was observed for the internalized fluorescent dextran or horseradish peroxidase initially stored in the lysosomal/endosomal compartment. The suppression of Neu1 expression in the THP-1-derived macrophages by small interfering RNA or with anti-Neu1 antibodies significantly reduced the ability of the cells to engulf bacteria or to produce cytokines. Altogether our data suggest that the upregulation of the Neu1 expression is important for the primary function of macrophages and establish the link between Neu1 and the cellular immune response. Human sialidase (neuraminidase) Neu1 catalyzes lysosomal catabolism of sialylated glycoconjugates. Here we show that during the differentiation of monocytes and the monocytic cell line, THP-1, into macrophages, the majority of Neu1 relocalizes from the lysosomes to the cell surface. In contrast to other cellular sialidases Neu2, Neu3, and Neu4, whose expression either remains unchanged or is down-regulated, Neu1 mRNA, protein and activity are specifically increased during the phorbol 12-myristate 13-acetate-induced differentiation, consistent with a significant induction of the transcriptional activity of the Neu1 gene promoter. The lysosomal carboxypeptidase, cathepsin A, which forms a complex with and activates Neu1 in the lysosome, is sorted to the plasma membrane of the differentiating cells similarly to Neu1. Both proteins are first targeted to the lysosome and then are sorted to the LAMP-2-negative, major histo-compatibility complex II-positive vesicles, which later merge with the plasma membrane. Similar trafficking was observed for the internalized fluorescent dextran or horseradish peroxidase initially stored in the lysosomal/endosomal compartment. The suppression of Neu1 expression in the THP-1-derived macrophages by small interfering RNA or with anti-Neu1 antibodies significantly reduced the ability of the cells to engulf bacteria or to produce cytokines. Altogether our data suggest that the upregulation of the Neu1 expression is important for the primary function of macrophages and establish the link between Neu1 and the cellular immune response. Human lysosomal sialidase (neuraminidase) Neu1, encoded by the NEU1 gene in the major histocompatibility complex III locus (1Pshezhetsky A.V. Richard C. Michaud L. Igdoura S. Wang S. Elsliger M.A. Qu J. Leclerc D. Gravel R. Dallaire L. Potier M. Nat. Genet. 1997; 15: 316-320Crossref PubMed Scopus (186) Google Scholar, 2Bonten E. van der Spoel A. Fornerod M. Grosveld G. d'Azzo A. 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The dissociation of the complex in vitro results in the reversible inactivation of Neu1 (6van der Horst G.T. Galjart N.J. d'Azzo A. Galjaard H. Verheijen F.W. J. Biol. Chem. 1989; 264: 1317-1322Abstract Full Text PDF PubMed Google Scholar). In vivo, inherited mutations in cathepsin A cause disruption of the complex and trigger galactosialidosis (OMIM 256540), an autosomal recessive disease characterized by combined deficiency of Neu1, β-galactosidase, and cathepsin A (reviewed in Ref. 4d'Azzo A. Andria G. Strisciuglio G. Galjaard H. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Inc., New York2001: 3811-3826Google Scholar). Another autosomal recessive disease, sialidosis (OMIM 256550), is caused by mutations directly affecting the NEU1 gene (reviewed in Refs. 7Thomas G.H. Beaudet A.L. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Inc., New York2001: 3507-3534Google Scholar and 8Seyrantepe V. Poupetova H. Froissart R. Zabot M.T. Maire I. Pshezhetsky A.V. Hum. Mutat. 2003; 22: 343-352Crossref PubMed Scopus (125) Google Scholar). We have previously shown that in addition to the lysosomes, Neu1 is also present on the surface of activated T cells (9Lukong K.E. Seyrantepe V. Landry K. Trudel S. Ahmad A. Gahl W.A. Lefrancois S. Morales C.R. Pshezhetsky A.V. J. Biol. Chem. 2001; 276: 46172-46181Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), where it may influence the immune function (10Chen X.P. Enioutina E.Y. Daynes R.A. J. Immunol. 1997; 158: 3070-3080PubMed Google Scholar, 11Chen X.P. Ding X. Daynes R.A. Cytokine. 2000; 12: 972-985Crossref PubMed Scopus (29) Google Scholar, 12Wang P. Zhang J. Bian H. Wu P. Kuvelkar R. Kung T.T. Crawley Y. Egan R.W. Billah M.M. Biochem. J. 2004; 380: 425-433Crossref PubMed Scopus (48) Google Scholar). Recently (13Stamatos N.M. Liang F. Nan X. Landry K. Cross A.S. Wang L.-X. Pshezhetsky A.V. FEBS J. 2005; 272: 2545-2556Crossref PubMed Scopus (58) Google Scholar), we have demonstrated that endogenous Neu1 sialidase activity of freshly isolated human monocytes is increased 20-30-fold per cell as they into an important cellular component of the an in the and of and immune The differentiation of monocytes into macrophages in is an for the of the of the and the of the Neu1 during the differentiation into the cellular immune and may to for Here we have the of the Neu1 expression and that the NEU1 gene is activated during the monocytic We have also shown that the Neu1 is first targeted to the lysosomes and as a complex with cathepsin A, relocalizes to the cell where it in or of and of cells isolated by of from human and and by from cells by an and then by a to the The of monocytes as by the cells with antibodies to and from and was as by of macrophages, monocytes in containing human and in in a the cells by with major histocompatibility horseradish and the differentiating macrophages and monocytes as by in by with a cell The cells to have cell surface by and of in S. M. Y. Y. K. J. PubMed Scopus Google Scholar), in the containing of and from The cells in The differentiation of cells into cells with as a in vitro for differentiation M. M. A. G. PubMed Scopus Google Scholar, J. Biochem. PubMed Scopus Google Scholar) was by the addition of to the the differentiating macrophages by as of the of the NEU1 gene by the of with and The into M. M. A. G. PubMed Scopus Google Scholar), by L. in of a in and containing β-galactosidase gene by R. Gravel of cells in a of in with of and in with the and expression in with the cells in a of with the and expression in with the the the cells with and for with per or in the or of or from In a and in the the addition of or the cells with by and in of and for and by in and β-galactosidase and as J. Biochem. PubMed Scopus Google Scholar). of activity is as the of of to M.M. Biochem. PubMed Scopus Google Scholar) with as a β-galactosidase, and in cellular and in the M. L. M. Dallaire L. Biochem. PubMed Scopus Google Scholar, M.M. Full Text PDF PubMed Scopus Google Scholar). A activity was with J. Michaud L. Potier M. Biochem. Res. PubMed Scopus Google Scholar). and as H. K. M. of Scholar, E. of Google Scholar, Ashmarina J. Biochem. PubMed Scopus Google Scholar). activity was as K. A. J. 10: PubMed Scopus Google Scholar, M. Biol. Chem. PubMed Scopus (48) Google Scholar) in the of The of sialic acid was by the R. Smith K. in Molecular Inc., New Scholar). activity is as the of of the on the cell the cells with and with of and either sialidase cathepsin A β-galactosidase or of of and the of the as The of plasma membrane was by by the of the into the cell during the We that the of was from the cells in and the of the was in the of of and Neu1 on the by cells and THP-1-derived macrophages by and for in of containing a acid a of with a The cells with and in of The cell by a was on a and the was by the the proteins with of The of the was to with of protein from the cell and the and of protein from the on a and to a membrane. The membrane was with the anti-Neu1 antibodies and A antibodies was a of and cells in containing in a with fluorescent dextran Inc., in a of or the horseradish peroxidase in a of cells in a of for the cells by a and with and in the containing of cells with of as with and with in for and by cells with and with anti-Neu1 or A antibodies and with antibodies also with antibodies Neu1 or cathepsin A antibodies and antibodies Inc., or The primary antibodies with antibodies The cells with the with the antibodies also with the anti-Neu1 or A antibodies with antibodies and antibodies or antibodies on a by and to a membrane. Neu1 and was with antibodies as (13Stamatos N.M. Liang F. Nan X. Landry K. Cross A.S. Wang L.-X. Pshezhetsky A.V. FEBS J. 2005; 272: 2545-2556Crossref PubMed Scopus (58) Google Scholar, Michaud L. A.V. K.E. M. Morales C.R. Potier M. Pshezhetsky A.V. Biochem. J. PubMed Scopus Google Scholar), and was with antibodies the in with the RNA and cells and THP-1-derived macrophages as previously and RNA was isolated the by the The RNA was with for to the and then by to the of RNA was to in the of of and of was to for was on a the The of and RNA are shown in which also the of the for we for the in The of the was by the of and on RNA from cells and THP-1-derived macrophages was by and to membrane The membrane was with the a from by an Neu1 a from a by and an of human with by of the was for in The directly to the and for The for with and for with and to a Neu1 RNA in Human and and of the human NEU1 from cells with the to the by the was as a for the of The was in where cells and with Neu1 and the sialidase activity was with acid as The Neu1 was to the suppression The expression of the Neu1 in the cells was on the RNA and protein by and activity as sialidase activity in the Neu1 cells was reduced then as with cells of cells was by in the of either anti-Neu1 or and of cells with Neu1 in the of cells on with in a of with with for with and with in with and with in on the of and in by to the of anti-Neu1 on the of and cells in a with in the and in the of or the human Neu1 and of a the cells for by and also in the and in the of or anti-Neu1 The of and in the was by an Neu1 during of a monocytic cell from the of a with monocytic S. 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Full Text Full Text PDF PubMed Scopus Google Scholar) Neu1 and A to the during the of and Human of Neu1 in the cells and the THP-1-derived macrophages was by In the Neu1 a with the lysosomal the induction with the of anti-Neu1 was significantly and The cells of Neu1, with and the other cells of macrophages, the majority of Neu1 was on the of the the the of Neu1 on the surface of the differentiating we a of the cells with anti-Neu1 antibodies and antibodies the cell surface The cells show for on the and the of differentiation, the cells expression of Neu1 and on surface Similar results also for surface and in the isolated human primary monocytes and the macrophages and In the lysosome, Neu1 is a component of a multienzyme which also the lysosomal carboxypeptidase A cathepsin A or protein), β-galactosidase, and sulfatase (reviewed in Refs. 4d'Azzo A. Andria G. Strisciuglio G. Galjaard H. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Inc., New York2001: 3811-3826Google Scholar and 5Pshezhetsky A.V. Ashmarina M. Prog. Nucleic Acids Res. Mol. Biol. 2001; 69: 81-114Crossref PubMed Scopus (111) Google Scholar). the complex is Neu1 activity and is by the lysosomal (6van der Horst G.T. Galjart N.J. d'Azzo A. Galjaard H. Verheijen F.W. J. Biol. Chem. 1989; 264: 1317-1322Abstract Full Text PDF PubMed Google Scholar, Michaud L. A.V. K.E. M. Morales C.R. Potier M. Pshezhetsky A.V. Biochem. J. PubMed Scopus Google Scholar). we that during the differentiation of cells and isolated a significant of cathepsin A is also targeted to the cell surface. In the cells as as in the primary human cathepsin A is in the lysosomes, with and Neu1 from the first of the differentiation and in the macrophages, cathepsin A is on the cell where it with the and and Neu1 The of Neu1 and cathepsin A from the lysosomes to the cell surface during the differentiation of monocytes and cells was also consistent with the results of the on the cell cells or THP-1-derived macrophages in an containing the the the was in the of In the the majority of Neu1 was the the activity was for the for the cells In in the THP-1-derived macrophages, the majority of Neu1 was present on the cell the activity was increased by the cells with the differentiation, the sialidase activity in the cell increased the sialidase activity on the surface increased In the activity of a lysosomal was in the and and in of the was for the in the of that the of the and cells was for macrophages and We an of the cathepsin A activity during the of the activity in macrophages was on the cell surface as to of the activity in the cells activity the of the component of the multienzyme lysosomal β-galactosidase, during the proteins on the surface of cells and the THP-1-derived macrophages and on a of protein from the cell and the and of the proteins from the by the anti-Neu1 antibodies and the antibodies the of cathepsin A In the Neu1 and cathepsin A in the containing in the THP-1-derived macrophages, a significant of was that they are present on the cell surface The of of the with the of Neu1 and cathepsin A are activated in the lysosome Michaud L. 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Similar for the lysosomal carboxypeptidase, cathepsin A, whose with Neu1 is for the of Neu1 in the Both Neu1 and cathepsin A are sorted from the to the the majority of lysosomal cathepsin A is targeted the K.E. Elsliger M.A. Potier M. Pshezhetsky A.V. PubMed Scopus Google Scholar), the trafficking of Neu1 is by the proteins a in (9Lukong K.E. Seyrantepe V. Landry K. Trudel S. Ahmad A. Gahl W.A. Lefrancois S. Morales C.R. Pshezhetsky A.V. J. Biol. Chem. 2001; 276: 46172-46181Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). In the lysosome, the proteins The of cathepsin A by a lysosomal which a between the of the Galjart N.J. R. M. d'Azzo A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The that the of Neu1 is it a of the Neu1 the of the complex with cathepsin A. We that in the differentiating are first targeted to the where they activity and then are sorted to the to the plasma membrane. 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In the differentiating the dextran and in the of on the cell plasma membrane in with Neu1 and cathepsin A. the suppression of Neu1 expression in the THP-1-derived macrophages by or with anti-Neu1 antibodies significantly reduced the of the as the ability to engulf bacteria or to produce that the of the Neu1 expression is important for of macrophages and the link between Neu1 and cellular immune response. the of the lysosomal Neu1, and the lysosomal carboxypeptidase, cathepsin A, to the plasma membrane is also important for other of the macrophages in for the of the cell surface may also important for the of macrophages with other cells with and cells sialic (reviewed in Ref. Biol. 12: PubMed Scopus Google Scholar). macrophages are present in cells in the cells in it is that of the NEU1 gene is important for differentiation, then the primary or deficiency of the Neu1 activity may of cells and cause in and We for in the of the and and Ashmarina for with

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