| SIGLEC6 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | SIGLEC6, CD327, CD33L, CD33L1, CD33L2, CDW327, OBBP1, sialic acid binding Ig like lectin 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:604405;HomoloGene:130495;GeneCards:SIGLEC6;OMA:SIGLEC6 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Sialic acid-binding Ig-like lectin 6 is aprotein that in humans is encoded by theSIGLEC6gene.[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 theSIGLEC family of receptors to be identified.[4] The protein has also been given theCD designation CD327.[5]
Siglec-6 was first found to be expressed in placental tissue,[3] which was confirmed when this protein was independently identified in a screen forleptin-binding proteins.[4] Using a newly generatedmonoclonal 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 humanhematopoietic cell lines, includingTF-1,HEL,U937, andTHP-1 cells. Thismonoclonal antibody also bound to nearly all human peripheral bloodB cells, although more recent reports have not replicated this finding.[6][7] Siglec-6 has also been found to be highly expressed on humanmast cells, including primaryCD34+ progenitor cell-derivedmast cells and the LAD2 cell line.[8] Examining theproteome ofmast cells from several tissues, it was determined that Siglec-6 is consistently expressed onmast cells from a variety of humantissues, includingadipose,skin,lung, andcolon, at relatively high levels.[7] Siglec-6 was not detected on any peripheral bloodleukocytes. 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, ROSAKITWT, and ROSAKITD816V, regardless ofKIT mutation status, even when cell-surface expression of the related receptorSiglec-8 is lost.[9] In addition,single-cell RNAseq of esophageal biopsies from patients witheosinophilic 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 thanmast cells, Siglec-6 expression has been detected on exhausted tissue-likeB cells[6] and a minor population ofdendritic cells (DCs) known asAXL+ 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 ofCAR T cell therapy.[11][12][13]
Siglec-6 was identified in a screen forleptin-binding proteins, although it interacted withleptin with reduced affinity relative to theleptin receptor.[4] As a member of theSiglec family of receptors with a conservedarginine residue necessary forsialic acid binding, Siglec-6 was expected to interact with its ligands in asialic acid-dependent manner. However, leptin is not sialylated,[14][15] and binding to Siglec-6 must therefore besialic acid independent. The physiological relevance of this interaction has not been determined.Glycodelin A binding totrophoblast cell lines was found to be dependent onsialic acid and competitive withleptin binding.[16]Glycodelin Aco-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 ofsialic acid fromglycodelin A. Neither the relevantsialic acidlinkage nor the remainder of theglycan structure onglycodelin A necessary for Siglec-6 binding are known. No physiological Siglec-6 ligands with apparent connections tomast cell biology have been identified. Initial studies found that Siglec-6 binds to sialyl-Tn antigen (Neu5Acα2–6GalNAcα) but not toTn 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 theSiglec family, requires thecarboxyl group onsialic acid, but is unique in that it does not require the glycolyl group ofsialic acid for binding.[17]
Siglec-6 contains in its cytoplasmic domain two known signaling motifs identified as animmunoreceptor 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 animmunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor through the recruitment and activation of protein tyrosine phosphatases likeSHP-1/2.
By introducing mutated versions of Siglec-6 lacking the keytyrosine residues in theITIM, the ITSM, or both into atrophoblast 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 recruitSHP-2 upon phosphorylation of these motifs.[18] Furthermore, binding ofglycodelin A totrophoblast cell lines was found to reduceERK1/2 phosphorylation,c-Jun protein and mRNA levels,MMP2 anduPA mRNA levels, and invasiveness in asialic acid- and Siglec-6-dependent manner, suggesting that Siglec-6 reducestrophoblast invasiveness in response to encounteringglycodelin A expression in thedecidualized endometrium.[16]
Antibody ligation of Siglec-6 on humanCD34+ progenitor-derived mast cells inhibitedGM-CSF secretion and slightly reduceddegranulation in response toIgE crosslinking, althoughIL-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 theG protein-coupled receptorsMRGPRX2 andC5aR, in addition to the ITAM-bearingFcεRI.[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 ofstreptavidin-based tetramers of antibodies targeting Siglec-6 andFcεRI.[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.
Knockdown of SIGLEC6 usingsiRNA in exhausted tissue-likeB cells fromHIV-infected individuals enhances the ability of these cells to proliferate or secreteCCL3 orIL-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.
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
