SIGLEC6

Last updated
SIGLEC6
Identifiers
Aliases SIGLEC6 , CD327, CD33L, CD33L1, CD33L2, CDW327, OBBP1, sialic acid binding Ig like lectin 6
External IDs OMIM: 604405 HomoloGene: 130495 GeneCards: SIGLEC6
Orthologs
SpeciesHumanMouse
Entrez

946

n/a

Ensembl

ENSG00000105492

n/a

UniProt

O43699

n/a

RefSeq (mRNA)

n/a

RefSeq (protein)

n/a

Location (UCSC) Chr 19: 51.52 – 51.53 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Sialic acid-binding Ig-like lectin 6 is a protein that in humans is encoded by the SIGLEC6 gene. [3] The gene was originally named CD33L (CD33-like) due to similarities between these genes but later became known as OB-BP1 (OB [leptin]-binding protein 1) due to its ability to bind to this factor and, finally, SIGLEC6 as the sixth member of the SIGLEC family of receptors to be identified. [4] The protein has also been given the CD designation CD327. [5]

Contents

Expression

Siglec-6 was first found to be expressed in placental tissue, [3] which was confirmed when this protein was independently identified in a screen for leptin-binding proteins. [4] Using a newly generated monoclonal antibody against Siglec-6 to detect protein expression, this latter study found that Siglec-6 was expressed by placental cytotrophoblasts and syncytiotrophoblasts as well as several human hematopoietic cell lines, including TF-1, HEL, U937, and THP-1 cells. This monoclonal antibody also bound to nearly all human peripheral blood B cells, although more recent reports have not replicated this finding. [6] [7] Siglec-6 has also been found to be highly expressed on human mast cells, including primary CD34+ progenitor cell-derived mast cells and the LAD2 cell line. [8] Examining the proteome of mast cells from several tissues, it was determined that Siglec-6 is consistently expressed on mast cells from a variety of human tissues, including adipose, skin, lung, and colon, at relatively high levels. [7] Siglec-6 was not detected on any peripheral blood leukocytes. Siglec-6 expression on human mast cells has since been extended to those isolated and cultured from skin and the mast cell lines HMC-1.2, LUVA, ROSA KITWT, and ROSA KITD816V, regardless of KIT mutation status, even when cell-surface expression of the related receptor Siglec-8 is lost. [9] In addition, single-cell RNAseq of esophageal biopsies from patients with eosinophilic esophagitis or healthy control subjects reveals that SIGLEC6 transcript is only detected in mast cells and not in any other cell types in this tissue. [9] Other than mast cells, Siglec-6 expression has been detected on exhausted tissue-like B cells [6] and a minor population of dendritic cells (DCs) known as AXL+ SIGLEC6+ (AS) DCs. [10] Siglec-6 has also been found on chronic lymphocytic leukemia and acute myeloid leukemia cells and is being explored as a target of CAR T cell therapy. [11] [12] [13]

Ligand binding

Siglec-6 was identified in a screen for leptin-binding proteins, although it interacted with leptin with reduced affinity relative to the leptin receptor. [4] As a member of the Siglec family of receptors with a conserved arginine residue necessary for sialic acid binding, Siglec-6 was expected to interact with its ligands in a sialic acid-dependent manner. However, leptin is not sialylated, [14] [15] and binding to Siglec-6 must therefore be sialic acid independent. The physiological relevance of this interaction has not been determined. Glycodelin A binding to trophoblast cell lines was found to be dependent on sialic acid and competitive with leptin binding. [16] Glycodelin A co-immunoprecipitated with chimeric Siglec-6-Fc protein in this study, indicating a direct interaction between the proteins, which was also reduced upon the enzymatic removal of sialic acid from glycodelin A. Neither the relevant sialic acid linkage nor the remainder of the glycan structure on glycodelin A necessary for Siglec-6 binding are known. No physiological Siglec-6 ligands with apparent connections to mast cell biology have been identified. Initial studies found that Siglec-6 binds to sialyl-Tn antigen (Neu5Acα2–6GalNAcα) but not to Tn antigen (GalNAcα), 6′-sialyl-lactose (Neu5Acα2–6Galβ1–4Glc), or 3′-sialyl-lactose (Neu5Acα2–3Galβ1–4Glc). [4] Further characterization of the glycan binding specificity of Siglec-6 revealed that Siglec-6, consistent with other members of the Siglec family, requires the carboxyl group on sialic acid, but is unique in that it does not require the glycolyl group of sialic acid for binding. [17]

Signaling and function

Siglec-6 contains in its cytoplasmic domain two known signaling motifs identified as an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). [4] Based on the presence of these motifs, it was presumed that Siglec-6 exerts an inhibitory effect on signaling cascades initiated by an immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor through the recruitment and activation of protein tyrosine phosphatases like SHP-1/2.

Placental trophoblasts

By introducing mutated versions of Siglec-6 lacking the key tyrosine residues in the ITIM, the ITSM, or both into a trophoblast cell line and treating the cell with the phosphatase inhibitor pervanadate, it was determined that both motifs are capable of being phosphorylated and that Siglec-6 is able to recruit SHP-2 upon phosphorylation of these motifs. [18] Furthermore, binding of glycodelin A to trophoblast cell lines was found to reduce ERK1/2 phosphorylation, c-Jun protein and mRNA levels, MMP2 and uPA mRNA levels, and invasiveness in a sialic acid- and Siglec-6-dependent manner, suggesting that Siglec-6 reduces trophoblast invasiveness in response to encountering glycodelin A expression in the decidualized endometrium. [16]

Mast cells

Antibody ligation of Siglec-6 on human CD34+ progenitor-derived mast cells inhibited GM-CSF secretion and slightly reduced degranulation in response to IgE crosslinking, although IL-8 secretion in response to stimulation was not similarly affected. [19] This observation of Siglec-6 inhibitory function on mast cells was expanded to human skin-derived mast cells and the G protein-coupled receptors MRGPRX2 and C5aR, in addition to the ITAM-bearing FcεRI. [9] Antibody ligation of Siglec-6 reduced mast cell degranulation in response to lower levels of the stimuli that act through these receptors. However, much more potent inhibition was observed by co-crosslinking Siglec-6 and FcεRI through the use of a secondary crosslinking antibody or the use of streptavidin-based tetramers of antibodies targeting Siglec-6 and FcεRI. [9] Additionally, the inhibitory effect of Siglec-6 ligation remained for at least 4.5 hours, perhaps due to the observed stability of the receptor on the cell surface following antibody ligation, suggesting that the receptor may continue to participate in inhibitory signaling for prolonged periods of time.

Exhausted tissue-like B cells

Knockdown of SIGLEC6 using siRNA in exhausted tissue-like B cells from HIV-infected individuals enhances the ability of these cells to proliferate or secrete CCL3 or IL-6 upon stimulation. [6] The lack of known Siglec-6 ligand in this system suggests that Siglec-6 may be reducing responsiveness of these cells through tonic signaling.


Related Research Articles

<span class="mw-page-title-main">Mast cell</span> Cell found in connective tissue

A mast cell is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumors.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

MAFA is a type II membrane glycoprotein, first identified on the surface of rat mucosal-type mast cells of the RBL-2H3 line. More recently, human and mouse homologues of MAFA have been discovered yet also expressed by NK and T-cells. MAFA is closely linked with the type 1 Fcɛ receptors in not only mucosal mast cells of humans and mice but also in the serosal mast cells of these same organisms.

<span class="mw-page-title-main">B-cell receptor</span> Transmembrane protein on the surface of a B cell

The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, and is typically located on the outer surface of these lymphocyte cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.

<span class="mw-page-title-main">Tyrosine-protein kinase SYK</span>

Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the SYK gene.

Sialyl-Lewis <sup>X</sup> Chemical compound

Sialyl LewisX (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide carbohydrate which is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. It is also the means by which an egg attracts sperm; first, to stick to it, then bond with it and eventually form a zygote.

Siglecs(Sialic acid-binding immunoglobulin-type lectins) are cell surface proteins that bind sialic acid. They are found primarily on the surface of immune cells and are a subset of the I-type lectins. There are 14 different mammalian Siglecs, providing an array of different functions based on cell surface receptor-ligand interactions.

<span class="mw-page-title-main">CD22</span> Lectin molecule

CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.

<span class="mw-page-title-main">CD33</span> Mammalian protein found in Homo sapiens

CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.

An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family found on immune cells. These immune cells include T cells, B cells, NK cells, dendritic cells, macrophages and mast cells. ITIMs have similar structures of S/I/V/LxYxxI/V/L, where x is any amino acid, Y is a tyrosine residue that can be phosphorylated, S is the amino acid serine, I is the amino acid isoleucine, and V is the amino acid valine. ITIMs recruit SH2 domain-containing phosphatases, which inhibit cellular activation. ITIM-containing receptors often serve to target immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in regulation of immune system allowing negative regulation at different levels of the immune response.

<span class="mw-page-title-main">SIGLEC7</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 7 is a protein that in humans is encoded by the SIGLEC7 gene. SIGLEC7 has also been designated as CD328.

<span class="mw-page-title-main">Sialic acid-binding Ig-like lectin 12</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 12, or Siglec-XII, is a protein that in humans, is encoded by the SIGLEC12 gene.

<span class="mw-page-title-main">SIGLEC5</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 5 is a protein that in humans is encoded by the SIGLEC5 gene. SIGLEC5 has also been designated CD170.

<span class="mw-page-title-main">SIGLEC9</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 9 is a protein that in humans is encoded by the SIGLEC9 gene.

<span class="mw-page-title-main">SIGLEC8</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 8 is a protein that in humans is encoded by the SIGLEC8 gene. This gene is located on chromosome 19q13.4, about 330 kb downstream of the SIGLEC9 gene. Within the siglec family of transmembrane proteins, Siglec-8 belongs to the CD33-related siglec subfamily, a subfamily that has undergone rapid evolution.

<span class="mw-page-title-main">PILRB</span> Protein-coding gene in the species Homo sapiens

Paired immunoglobulin-like type 2 receptor beta is a protein that in humans is encoded by the PILRB gene.

<span class="mw-page-title-main">SIGLEC10</span> Protein-coding gene in the species Homo sapiens

Sialic acid-binding Ig-like lectin 10 is a protein that in humans is encoded by the SIGLEC10 gene. Siglec-G is often referred to as the murine paralog of human Siglec-10

<span class="mw-page-title-main">PILRA</span> Protein-coding gene in the species Homo sapiens

Paired immunoglobin like type 2 receptor alpha is a protein that in humans is encoded by the PILRA gene.

Lirentelimab is a humanized nonfucosylated monoclonal antibody that targets sialic acid-binding Ig-like lectin 8 (SIGLEC8). In a randomized clinical trial, lirentelimab was found to improve eosinophil counts and symptoms in individuals with eosinophilic gastritis and duodenitis. Adverse reactions include infusion reactions, which are mild to moderate and typically occur following the first infusion.

<span class="mw-page-title-main">Paired receptors</span>

Paired receptors are pairs or clusters of receptor proteins that bind to extracellular ligands but have opposing activating and inhibitory signaling effects. Traditionally, paired receptors are defined as homologous pairs with similar extracellular domains and different cytoplasmic regions, whose genes are located together in the genome as part of the same gene cluster and which evolved through gene duplication. Homologous paired receptors often, but not always, have a shared ligand in common. More broadly, pairs of receptors have been identified that exhibit paired functional behavior - responding to a shared ligand with opposing intracellular signals - but are not closely homologous or co-located in the genome. Paired receptors are highly expressed in the cells of the immune system, especially natural killer (NK) and myeloid cells, and are involved in immune regulation.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000105492 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 Takei Y, Sasaki S, Fujiwara T, Takahashi E, Muto T, Nakamura Y (1997). "Molecular cloning of a novel gene similar to myeloid antigen CD33 and its specific expression in placenta". Cytogenetic and Genome Research. 78 (3–4): 295–300. doi:10.1159/000134676. PMID   9465907.
  4. 1 2 3 4 5 Patel N, Brinkman-Van der Linden EC, Altmann SW, Gish K, Balasubramanian S, Timans JC, Peterson D, Bell MP, Bazan JF, Varki A, Kastelein RA (August 1999). "OB-BP1/Siglec-6. a leptin- and sialic acid-binding protein of the immunoglobulin superfamily". Journal of Biological Chemistry. 274 (32): 22729–38. doi: 10.1074/jbc.274.32.22729 . PMID   10428856.
  5. ↑ Zola H, Swart B, Banham A, Barry S, Beare A, Bensussan A, Boumsell L, Buckley CD, Buhring HJ, Clark G, Engel P, Fox D, Jin BQ, Macardle PJ, Malavasi F, Mason D, Stockinger H, Yang X (January 2007). "CD molecules 2006--human cell differentiation molecules". Journal of Immunological Methods. 319 (1–2): 1–5. doi:10.1016/j.jim.2006.11.001. PMID   17174972.
  6. 1 2 3 Kardava L, Moir S, Wang W, Ho J, Buckner CM, Posada JG, O'Shea MA, Roby G, Chen J, Sohn HW, Chun TW, Pierce SK, Fauci AS (July 2011). "Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors". Journal of Clinical Investigation. 121 (7): 2614–24. doi:10.1172/JCI45685. PMC   3127436 . PMID   21633172.
  7. 1 2 Plum T, Wang X, Rettel M, Krijgsveld J, Feyerabend TB, Rodewald HR (February 2020). "Human Mast Cell Proteome Reveals Unique Lineage, Putative Functions, and Structural Basis for Cell Ablation". Immunity. 52 (2): 404–416. doi: 10.1016/j.immuni.2020.01.012 . PMID   32049054. S2CID   211086219.
  8. ↑ Yokoi H, Myers A, Matsumoto K, Crocker PR, Saito H, Bochner BS (June 2006). "Alteration and acquisition of Siglecs during in vitro maturation of CD34+ progenitors into human mast cells". Allergy. 61 (6): 769–76. doi:10.1111/j.1398-9995.2006.01133.x. PMID   16677248. S2CID   21873800.
  9. 1 2 3 4 Robida PA, Rische CH, Morgenstern NB-B, Janarthanam R, Cao Y, Krier-Burris RA, Korver W, Xu A, Luu T, Schanin J, Leung J, Rothenberg ME, Wechsler JB, Youngblood BA, Bochner BS, O'Sullivan JA (March 2022). "Functional and Phenotypic Characterization of Siglec-6 on Human Mast Cells". Cells. 11 (7): 1138. doi: 10.3390/cells11071138 . PMC   8997871 . PMID   35406705.
  10. ↑ Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, Griesbeck M, Butler A, Zheng S, Lazo S, Jardine L, Dixon D, Stephenson E, Nilsson E, Grundberg I, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A, Hacohen N (April 2017). "Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors". Science. 356 (6335): eaah4573. doi:10.1126/science.aah4573. hdl:1721.1/116797. PMC   5775029 . PMID   28428369. S2CID   31380838.
  11. ↑ Chang J, Peng H, Shaffer BC, Baskar S, Wecken IC, Cyr MG, Martinez GJ, Soden J, Freeth J, Wiestner A, Rader C (September 2018). "Siglec-6 on Chronic Lymphocytic Leukemia Cells Is a Target for Post-Allogeneic Hematopoietic Stem Cell Transplantation Antibodies". Cancer Immunology Research. 6 (9): 1008–1013. doi:10.1158/2326-6066.CIR-18-0102. PMC   6125214 . PMID   29980538.
  12. ↑ Kovalovsky D, Yoon JH, Cyr MG, Simon S, Voynova E, Rader C, Wiestner A, Alejo J, Pittaluga S, Gress RE (September 2021). "Siglec-6 is a target for chimeric antigen receptor T-cell treatment of chronic lymphocytic leukemia". Leukemia. 35 (9): 2581–2591. doi:10.1038/s41375-021-01188-3. PMC   8384967 . PMID   33633313. S2CID   232044054.
  13. ↑ Jetani H, Navarro-Bailon A, Maucher M, Frenz S, Verbruggen C, Yeguas A, Vidriales MB, Gonzalez M, Saborido JR, Kraus S, Mestermann K, Thomas S, Bonig H, Luu M, Monjezi R, Mougiakakos D, Sauer M, Einsele H, Hudacek M (November 2021). "Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia". Blood. 138 (19): 1830–1842. doi: 10.1182/blood.2020009192 . PMC   9642786 . PMID   34289026. S2CID   236175815.
  14. ↑ Cohen SL, Halaas JL, Friedman JM, Chait BT, Bennett L, Chang D, Hecht R, Collins F (August 1996). "Human leptin characterization". Nature. 382 (6592): 589. Bibcode:1996Natur.382Q.589C. doi: 10.1038/382589a0 . PMID   8757126. S2CID   28066268.
  15. ↑ Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (December 1994). "Positional cloning of the mouse obese gene and its human homologue". Nature. 372 (6505): 425–32. Bibcode:1994Natur.372..425Z. doi:10.1038/372425a0. PMID   7984236. S2CID   4359725.
  16. 1 2 Lam KKW, Chiu PCN, Lee C-L, Pang RTK, Leung CON, Koistinen H, Seppala M, Ho P-C, Yeung WSB (October 2011). "Glycodelin-A protein interacts with Siglec-6 protein to suppress trophoblast invasiveness by down-regulating extracellular signal-regulated kinase (ERK)/c-Jun signaling pathway". Journal of Biological Chemistry. 286 (43): 37118–27. doi: 10.1074/jbc.M111.233841 . PMC   3199459 . PMID   21880722.
  17. ↑ Brinkman-Van der Linden EC, Varki A (March 2000). "New aspects of siglec binding specificities, including the significance of fucosylation and of the sialyl-Tn epitope. Sialic acid-binding immunoglobulin superfamily lectins". Journal of Biological Chemistry. 275 (12): 8625–32. doi: 10.1074/jbc.275.12.8625 . PMID   10722702.
  18. ↑ Stefanski AL, Renecle MD, Rumer KK, Winn VD (March 2014). "Siglec-6 phosphorylation at intracellular tyrosine residues leads to the recruitment of SHP-2 phosphatase". Reproductive Sciences. 21 (3): 388A.
  19. ↑ Yu Y, Blokhuis BRJ, Diks MAP, Keshavarzian A, Garssen J, Redegeld FA (September 2018). "Functional Inhibitory Siglec-6 Is Upregulated in Human Colorectal Cancer-Associated Mast Cells". Frontiers in Immunology. 9: 2138. doi: 10.3389/fimmu.2018.02138 . PMC   6159741 . PMID   30294327.

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