Sialoadhesin

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Sialoadhesin (Sn) is an atypical siglec, due to the presence of an unusually large number of Ig domains (17) and the absence of tyrosine-based intracellular signaling motifs. Sn prefers NeuNAc in α2,3-linkage over α2,6 and α2,8 linkages but does not recognize NeuGc or NeuAc9Ac. Sn is expressed uniquely by macrophage subsets in vivo and the 17 Ig domains are thought to be important for its ability to mediate sialic acid-dependent adhesive functions. This contrasts with most other siglecs which are much shorter and masked by cis binding to co-expressed sialic acids. Sn contributes to proinflammatory immune responses in a variety of autoimmune diseases<ref>Jiang, H. R. et al. Sialoadhesin promotes the inflammatory response in experimental autoimmune uveoretinitis. J Immunol 177, 2258-2264 (2006).</ref><ref>Ip, C. W., Kroner, A., Crocker, P. R., Nave, K. A. & Martini, R. Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice. Neurobiol Dis 25, 105-111 (2007).</ref>, and this may be due to suppression of Treg expansion as demonstrated in experimental allergic encephalomyelitis, a model for multiple sclerosis<ref>Wu, C. et al. Sialoadhesin-positive macrophages bind regulatory T cells, negatively controlling their expansion and autoimmune disease progression. J Immunol 182, 6508-6516 (2009).</ref>. Sn has also been shown to function as a macrophage receptor for the porcine arterivirus<ref>Delputte, P. L. et al. Porcine arterivirus attachment to the macrophage-specific receptor sialoadhesin is
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Sialoadhesin (Sn), also known as Siglec-1, is an atypical siglec, due to the presence of an unusually large number of Ig domains (17) and the absence of tyrosine-based intracellular signaling motifs. Sn is expressed uniquely by macrophage subsets in vivo and the 17 Ig domains are thought to be important for its ability to mediate sialic acid-dependent adhesive functions. This contrasts with most other siglecs which are much shorter and masked by cis binding to co-expressed sialic acids.
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dependent on the sialic acid-binding activity of the N-terminal immunoglobulin domain of sialoadhesin. J Virol 81, 9546-9550 (2007).</ref> and can also promote macrophage uptake of sialylated bacteria such as ''Neisseria meningitidis''<ref>Jones, C., Virji, M. & Crocker, P. R. Recognition of sialylated meningococcal lipopolysaccharide by siglecs expressed on myeloid cells leads to enhanced bacterial uptake. Mol Microbiol 49, 1213-1225 (2003).</ref>.
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== CFG Participating Investigators contributing to the understanding of this paradigm ==
== CFG Participating Investigators contributing to the understanding of this paradigm ==
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== Progress toward understanding this GBP paradigm ==
== Progress toward understanding this GBP paradigm ==
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This section documents what is currently known about sialoadhesin, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_267&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Itlect_193&sideMenu=no mouse] sialoadhesin (a.k.a. Siglec-1) in the CFG database.
=== Carbohydrate ligands ===
=== Carbohydrate ligands ===
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[[File:Sia3Gal_small.png]]
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Sn is a fairly promiscuous receptor, with a preference for Sia&alpha;2-3Gal over Sia&alpha;2-6Gal terminated glycans. Sn prefers NeuNAc in α2,3-linkage over α2,6 and α2,8 linkages and does not recognize NeuGc or NeuAc9Ac. In pull-down experiments using Sn-Fc constructs, mucin-like proteins with multiple O-linked glycans seem to be preferred (eg CD43, Muc-1), but whether these represent preferred counterreceptors during cell-cell interactions between Sn+ macrophages and other cells is unknown
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<br>
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=== Cellular expression ===
 
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=== Cellular expression of GBP and ligands ===
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Sn is expressed exclusively by cells of the mononuclear phagocyte lineage, including in some cases myeloid dendritic cells as well as classic macrophages.  It is expressed constitutively by many tissue macrophages, particularly those in primary and secondary lymphoid organs and may play a role in antigen capture and tolerance.  Sn can also be induced on macrophages by IFN-&alpha; or agents that induce expression of IFN-&alpha; such as LPS or poly-I:C.  Ligands for Sn are regulated via expression of sialyltransferases and are found on many cells of the body.  Surveys of haemopoietic targets have identified granulocytes as being rich in Sn ligands but the functional significance of this is unclear at present.
<br>
<br>
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=== Structure ===
 
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=== Biosynthesis of ligands ===
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Due to the relatively wide specificity of Sialoadhesin, several enzymes can synthezise suitable glycans. Of particular importance are 2,3-sialyltransferases sialylating ''N''- and ''O''-glycans.<ref name="Crocker1991">Crocker PR, Kelm S, Dubois C, Martin B, McWilliam AS, Shotton DM, Paulson JC, Gordon S. (1991) Purification and properties of sialoadhesin, a sialic acid-binding receptor of murine tissue macrophages. EMBO J. 1991, 10, 1661-1669</ref> <ref name="Kelm1994">S. Kelm, A. Pelz, R. Schauer, M. T. Filbin, S. Tang, M.-E. de Bellard, R. L. Schnaar, J. A. Mahoney, A. Hartnell, P. Bradfield, P. R. Crocker (1994) Sialoadhesin, MAG and CD22 define a new family of sialic acid-dependent adhesion molecules of the immunoglobulin superfamily. Curr. Biol. 4, 965-972</ref> Furthermore, it is important to note that sialic acid modifying enzymes, such as CMP-Neu5Ac hydroxylase ''O''-acetyltransferases or 9-''O''-acetylsialate esterases, negtively control the biosynthesis of ligands for Sialoadhesin.<ref name="Kelm1994a">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. (1994)Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22.Glycoconj J. 1994 11, 576-85</ref> <ref name="Brinkman-Van der Linden2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. (2000) Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs. J. Biol. Chem. 2000, 275, 8633-8640</ref>
<br>
<br>
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=== Biological roles of GBP-ligand interaction ===
 
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=== Structure ===
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The crystal structure of the N-terminal carbohydrate-binding domain of sialoadhesin in complex with 3'-sialyllactose highlights the roles of three key conserved amino acids, tryptophan 2, arginine 97 and tryptophan 106, in the ligand-binding domains of the siglecs that are involved in interactions with the various characteristic groups that project from the pyranose ring of sialic acid. The structure provides a rationale for why sialoadhesin binds to N-acetyl- but not N-glycolyl neuraminic acid and the limited interactions with the lactose portion of the glycan are consistent with the ability of sialoadhesin to bind both 2-3 and 2-6 linked sialic acid.<ref name"Crocker1998">May, AP, Robinson, RC, Vinson, M, Crocker, PR and Jones, EY (1998) Crystal structure of the N-terminal domain of sialoadhesin in complex with 3  sialyllactose at 1.85 Å Resolution. Molecular Cell 1, 719-728</ref>
<br>
<br>
 +
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=== Biological roles of GBP-ligand interaction ===
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Sn contributes to proinflammatory immune responses in a variety of autoimmune diseases<ref>Jiang, H. R. et al. Sialoadhesin promotes the inflammatory response in experimental autoimmune uveoretinitis. J Immunol 177, 2258-2264 (2006).</ref><ref>Ip, C. W., Kroner, A., Crocker, P. R., Nave, K. A. & Martini, R. Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice. Neurobiol Dis 25, 105-111 (2007).</ref>, and this may be due to suppression of Treg expansion as demonstrated in experimental allergic encephalomyelitis, a model for multiple sclerosis<ref>Wu, C. et al. Sialoadhesin-positive macrophages bind regulatory T cells, negatively controlling their expansion and autoimmune disease progression. J Immunol 182, 6508-6516 (2009).</ref>. Sn has also been shown to function as a macrophage receptor for the porcine arterivirus<ref>Delputte, P. L. et al. Porcine arterivirus attachment to the macrophage-specific receptor sialoadhesin is
 +
dependent on the sialic acid-binding activity of the N-terminal immunoglobulin domain of sialoadhesin. J Virol 81, 9546-9550 (2007).</ref> and can also promote macrophage uptake of sialylated bacteria such as ''Neisseria meningitidis''<ref>Jones, C., Virji, M. & Crocker, P. R. Recognition of sialylated meningococcal lipopolysaccharide by siglecs expressed on myeloid cells leads to enhanced bacterial uptake. Mol Microbiol 49, 1213-1225 (2003).</ref>.
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<br>
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== CFG resources used in investigations ==
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Sialoadhesin&maxresults=20 CFG database search results for sialoadhesin].
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Sialoadhesin&maxresults=20 CFG database search results for sialoadhesin].
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=== Glycogene microarray ===
=== Glycogene microarray ===
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Probes for mouse and human sialoadhesin (under the name Siglec-1) have been included on all four versions of the CFG glycogene microarray.
<br>
<br>
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=== Knockout mouse lines ===
 
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=== Knockout mouse lines ===
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The CFG did not undertake creation of knockout mice for sialoadhesin because generation of such mice was already underway. Studies of these mice indicate a role for sialoadhesin in regulation of the cellular and humoral immune response<ref name=”Oetke2006”>Oetke C, Vinson MC, Jones C, Crocker PR (2006) Sialoadhesin-deficient mice exhibit subtle changes in B- and T-cell populations and reduced immunoglobulin M levels. Mol. Cell. Biol. 26, 1549-57</ref>
<br>
<br>
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=== Glycan array ===
=== Glycan array ===
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The CFG glycan array has been probed with both murine and porcine Sn constructs, but no positive signals were obtained, likely due to the low affinity of Sn for sialylated oligosaccharides.
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The CFG glycan array has been probed with both murine and porcine Sn constructs, but no positive signals were obtained (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1383 here]), likely due to the low affinity of Sn for sialylated oligosaccharides.
== Related GBPs ==
== Related GBPs ==
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== Acknowledgements ==
== Acknowledgements ==
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The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, James Paulson
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The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, Sorge Kelm, James Paulson

Current revision as of 21:02, 27 January 2012

Sialoadhesin (Sn), also known as Siglec-1, is an atypical siglec, due to the presence of an unusually large number of Ig domains (17) and the absence of tyrosine-based intracellular signaling motifs. Sn is expressed uniquely by macrophage subsets in vivo and the 17 Ig domains are thought to be important for its ability to mediate sialic acid-dependent adhesive functions. This contrasts with most other siglecs which are much shorter and masked by cis binding to co-expressed sialic acids.

Contents

CFG Participating Investigators contributing to the understanding of this paradigm

CFG Participating Investigators (PIs) contributing to the understanding of Sn include: Paul Crocker, Peter Delputte, Soerge Kelm, Ajit Varki

Progress toward understanding this GBP paradigm

This section documents what is currently known about sialoadhesin, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for human and mouse sialoadhesin (a.k.a. Siglec-1) in the CFG database.

Carbohydrate ligands

File:Sia3Gal_small.png

Sn is a fairly promiscuous receptor, with a preference for Siaα2-3Gal over Siaα2-6Gal terminated glycans. Sn prefers NeuNAc in α2,3-linkage over α2,6 and α2,8 linkages and does not recognize NeuGc or NeuAc9Ac. In pull-down experiments using Sn-Fc constructs, mucin-like proteins with multiple O-linked glycans seem to be preferred (eg CD43, Muc-1), but whether these represent preferred counterreceptors during cell-cell interactions between Sn+ macrophages and other cells is unknown

Cellular expression of GBP and ligands

Sn is expressed exclusively by cells of the mononuclear phagocyte lineage, including in some cases myeloid dendritic cells as well as classic macrophages. It is expressed constitutively by many tissue macrophages, particularly those in primary and secondary lymphoid organs and may play a role in antigen capture and tolerance. Sn can also be induced on macrophages by IFN-α or agents that induce expression of IFN-α such as LPS or poly-I:C. Ligands for Sn are regulated via expression of sialyltransferases and are found on many cells of the body. Surveys of haemopoietic targets have identified granulocytes as being rich in Sn ligands but the functional significance of this is unclear at present.

Biosynthesis of ligands

Due to the relatively wide specificity of Sialoadhesin, several enzymes can synthezise suitable glycans. Of particular importance are 2,3-sialyltransferases sialylating N- and O-glycans.[1] [2] Furthermore, it is important to note that sialic acid modifying enzymes, such as CMP-Neu5Ac hydroxylase O-acetyltransferases or 9-O-acetylsialate esterases, negtively control the biosynthesis of ligands for Sialoadhesin.[3] [4]

Structure

The crystal structure of the N-terminal carbohydrate-binding domain of sialoadhesin in complex with 3'-sialyllactose highlights the roles of three key conserved amino acids, tryptophan 2, arginine 97 and tryptophan 106, in the ligand-binding domains of the siglecs that are involved in interactions with the various characteristic groups that project from the pyranose ring of sialic acid. The structure provides a rationale for why sialoadhesin binds to N-acetyl- but not N-glycolyl neuraminic acid and the limited interactions with the lactose portion of the glycan are consistent with the ability of sialoadhesin to bind both 2-3 and 2-6 linked sialic acid.[5]

Biological roles of GBP-ligand interaction

Sn contributes to proinflammatory immune responses in a variety of autoimmune diseases[6][7], and this may be due to suppression of Treg expansion as demonstrated in experimental allergic encephalomyelitis, a model for multiple sclerosis[8]. Sn has also been shown to function as a macrophage receptor for the porcine arterivirus[9] and can also promote macrophage uptake of sialylated bacteria such as Neisseria meningitidis[10].

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for sialoadhesin.

Glycan profiling


Glycogene microarray

Probes for mouse and human sialoadhesin (under the name Siglec-1) have been included on all four versions of the CFG glycogene microarray.

Knockout mouse lines

The CFG did not undertake creation of knockout mice for sialoadhesin because generation of such mice was already underway. Studies of these mice indicate a role for sialoadhesin in regulation of the cellular and humoral immune response[11]

Glycan array

The CFG glycan array has been probed with both murine and porcine Sn constructs, but no positive signals were obtained (click here), likely due to the low affinity of Sn for sialylated oligosaccharides.

Related GBPs

None.

References

  1. Crocker PR, Kelm S, Dubois C, Martin B, McWilliam AS, Shotton DM, Paulson JC, Gordon S. (1991) Purification and properties of sialoadhesin, a sialic acid-binding receptor of murine tissue macrophages. EMBO J. 1991, 10, 1661-1669
  2. S. Kelm, A. Pelz, R. Schauer, M. T. Filbin, S. Tang, M.-E. de Bellard, R. L. Schnaar, J. A. Mahoney, A. Hartnell, P. Bradfield, P. R. Crocker (1994) Sialoadhesin, MAG and CD22 define a new family of sialic acid-dependent adhesion molecules of the immunoglobulin superfamily. Curr. Biol. 4, 965-972
  3. Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. (1994)Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22.Glycoconj J. 1994 11, 576-85
  4. Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. (2000) Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs. J. Biol. Chem. 2000, 275, 8633-8640
  5. May, AP, Robinson, RC, Vinson, M, Crocker, PR and Jones, EY (1998) Crystal structure of the N-terminal domain of sialoadhesin in complex with 3 sialyllactose at 1.85 Å Resolution. Molecular Cell 1, 719-728
  6. Jiang, H. R. et al. Sialoadhesin promotes the inflammatory response in experimental autoimmune uveoretinitis. J Immunol 177, 2258-2264 (2006).
  7. Ip, C. W., Kroner, A., Crocker, P. R., Nave, K. A. & Martini, R. Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice. Neurobiol Dis 25, 105-111 (2007).
  8. Wu, C. et al. Sialoadhesin-positive macrophages bind regulatory T cells, negatively controlling their expansion and autoimmune disease progression. J Immunol 182, 6508-6516 (2009).
  9. Delputte, P. L. et al. Porcine arterivirus attachment to the macrophage-specific receptor sialoadhesin is dependent on the sialic acid-binding activity of the N-terminal immunoglobulin domain of sialoadhesin. J Virol 81, 9546-9550 (2007).
  10. Jones, C., Virji, M. & Crocker, P. R. Recognition of sialylated meningococcal lipopolysaccharide by siglecs expressed on myeloid cells leads to enhanced bacterial uptake. Mol Microbiol 49, 1213-1225 (2003).
  11. Oetke C, Vinson MC, Jones C, Crocker PR (2006) Sialoadhesin-deficient mice exhibit subtle changes in B- and T-cell populations and reduced immunoglobulin M levels. Mol. Cell. Biol. 26, 1549-57

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, Sorge Kelm, James Paulson

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