# SIGLEC8

## Overview
SIGLEC8 is a gene located on chromosome 19q13.33-41 that encodes the protein sialic acid-binding Ig-like lectin 8 (Siglec-8), a type 1 transmembrane protein belonging to the immunoglobulin superfamily. Siglec-8 is primarily expressed on eosinophils, mast cells, and basophils, where it plays a significant role in modulating immune responses. The protein is characterized by its ability to bind sialic acid-containing glycans, particularly 6′-sulfo sialyl Lewis x, through its extracellular immunoglobulin-like domains. Functionally, Siglec-8 is involved in inducing apoptosis in eosinophils and inhibiting mediator release in mast cells, thereby contributing to immune regulation and homeostasis. The gene and its protein product have been implicated in various allergic and eosinophil-related diseases, such as asthma, and are of interest for their potential roles in disease pathogenesis and as therapeutic targets (Bochner2005Glycan; Floyd2000Siglec8; Nutku2003Ligation).

## Structure
Siglec-8 is a type 1 transmembrane protein belonging to the immunoglobulin superfamily, characterized by its ability to bind sialic acid-containing glycans. The protein is composed of 431 amino acids and features an extracellular region with three immunoglobulin-like domains: an N-terminal V-set domain and two C2-set domains (Floyd2000Siglec8). The extracellular region also includes a hydrophobic signal peptide and three potential N-linked glycosylation sites, which are common post-translational modifications (Floyd2000Siglec8). 

The structure of Siglec-8 includes a canonical V-set Ig-like β-sandwich fold, with a conserved disulfide bond and an essential arginine residue for sialic acid recognition (Pröpster2016Structural). The protein's binding site is characterized by a positively charged cleft formed by specific β-strands and unique loops, which are crucial for its interaction with its glycan ligand, 6′-sulfo sialyl Lewis x (Pröpster2016Structural). 

Siglec-8 lacks the conserved tyrosine-based motifs in its cytoplasmic tail, which distinguishes it from other related proteins (Floyd2000Siglec8). The gene encoding Siglec-8 is located on chromosome 19q13.33-41, in close proximity to other siglec genes (Floyd2000Siglec8).

## Function
SIGLEC8 is a protein expressed on human eosinophils, mast cells, and basophils, playing a crucial role in immune regulation. In eosinophils, SIGLEC8 engagement induces apoptosis, a process that involves caspase-3-like activity and is enhanced by cytokines such as IL-5 and GM-CSF (bochner2009siglec; Nutku2003Ligation). This apoptotic pathway involves mitochondrial dysfunction and the production of reactive oxygen species (Gunten2024Expression). The receptor's activity is not counteracted by proinflammatory cytokines, which instead enhance the sensitivity of eosinophils to SIGLEC8-mediated apoptosis (Pröpster2016Structural).

In mast cells, SIGLEC8 engagement does not induce apoptosis but inhibits FcεRI-dependent mediator release, such as histamine and prostaglandin D2, and affects calcium flux responses (bochner2009siglec; Yokoi2008Inhibition). This inhibition is linked to the cytoplasmic ITIM domain of SIGLEC8, suggesting a role in modulating immune responses by interfering with specific signaling pathways (Yokoi2008Inhibition). SIGLEC8's interaction with its glycan targets, particularly 6′-sulfo-sialyl Lewis X, is highly specific and crucial for its function in immune homeostasis (Bochner2005Glycan; Tateno2005Mouse).

## Clinical Significance
Mutations and alterations in the SIGLEC8 gene have been associated with several allergic and eosinophil-related diseases, particularly asthma. Genetic polymorphisms in SIGLEC8, such as SNPs rs36498 and rs10409962, have been linked to asthma susceptibility in various populations, including African Americans, Brazilians, and Japanese (Angata2014Associations; Gao2010Polymorphisms). The rs36498 SNP, located in the promoter region, has shown a protective effect against asthma, with the T allele being associated with reduced risk (Gao2010Polymorphisms; Sajayasbaghi2020Promoter). 

Alterations in SIGLEC8 expression levels have also been implicated in the pathogenesis of asthma. Siglec-8 engagement induces eosinophil apoptosis and inhibits mast cell activation, processes that are crucial in asthma pathophysiology (Sajayasbaghi2020Promoter). Additionally, the SNP rs6509541 in the 3′ untranslated region has been associated with serum IgE levels, suggesting a broader role for Siglec-8 in allergic diseases (Gao2010Polymorphisms).

In clear cell renal cell carcinoma (ccRCC), high Siglec-8 expression has been correlated with worse overall and disease-free survival, indicating its potential as a prognostic biomarker (Ou2017Enhancement).

## Interactions
SIGLEC8, a member of the sialic acid-binding immunoglobulin-like lectins family, is primarily expressed on eosinophils and mast cells. It interacts with the high-affinity IgE receptor (FcεRI) on mast cells, leading to the inhibition of intracellular signaling pathways. This interaction involves the recruitment of SH2-containing protein phosphatase Shp-2, which is dependent on the phosphorylation of SIGLEC8's immunoreceptor tyrosine-based inhibitory motifs (ITIMs). This process results in reduced mast cell activation and degranulation (Korver2022The).

SIGLEC8 also engages in interactions with sialylated cis ligands on the surface of eosinophils and mast cells. These cis interactions are thought to mask SIGLEC8, preventing it from binding to trans ligands and thereby restraining its ability to induce cell death. The removal of these cis ligands through sialidase treatment enhances SIGLEC8's capacity to induce apoptosis in eosinophils and mast cells, even in the absence of cytokine priming (Cao2023Interactions).

These interactions highlight SIGLEC8's role in modulating immune responses, particularly in the regulation of eosinophil survival and mast cell activation, which are critical in conditions such as allergies and asthma.


## References


1. (Gunten2024Expression) Expression and Function of Siglec-8 in Human Eosinophils, Basophils, and Mast Cells. This article has 3 citations.

[2. (Tateno2005Mouse) Hiroaki Tateno, Paul R. Crocker, and James C. Paulson. Mouse siglec-f and human siglec-8 are functionally convergent paralogs that are selectively expressed on eosinophils and recognize 6′-sulfo-sialyl lewis x as a preferred glycan ligand. Glycobiology, 15(11):1125–1135, June 2005. URL: http://dx.doi.org/10.1093/glycob/cwi097, doi:10.1093/glycob/cwi097. This article has 150 citations and is from a peer-reviewed journal.](https://doi.org/10.1093/glycob/cwi097)

[3. (Korver2022The) Wouter Korver, Alan Wong, Simon Gebremeskel, Gian Luca Negri, Julia Schanin, Katherine Chang, John Leung, Zachary Benet, Thuy Luu, Emily C. Brock, Kenneth Luehrsen, Alan Xu, and Bradford A. Youngblood. The inhibitory receptor siglec-8 interacts with fcεri and globally inhibits intracellular signaling in primary mast cells upon activation. Frontiers in Immunology, January 2022. URL: http://dx.doi.org/10.3389/fimmu.2022.833728, doi:10.3389/fimmu.2022.833728. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2022.833728)

[4. (Cao2023Interactions) Yun Cao, Clayton H. Rische, Bruce S. Bochner, and Jeremy A. O’Sullivan. Interactions between siglec-8 and endogenous sialylated cis ligands restrain cell death induction in human eosinophils and mast cells. Frontiers in Immunology, October 2023. URL: http://dx.doi.org/10.3389/fimmu.2023.1283370, doi:10.3389/fimmu.2023.1283370. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2023.1283370)

[5. (Pröpster2016Structural) Johannes M. Pröpster, Fan Yang, Said Rabbani, Beat Ernst, Frédéric H.-T. Allain, and Mario Schubert. Structural basis for sulfation-dependent self-glycan recognition by the human immune-inhibitory receptor siglec-8. Proceedings of the National Academy of Sciences, June 2016. URL: http://dx.doi.org/10.1073/pnas.1602214113, doi:10.1073/pnas.1602214113. This article has 67 citations.](https://doi.org/10.1073/pnas.1602214113)

[6. (Angata2014Associations) Takashi Angata. Associations of genetic polymorphisms of siglecs with human diseases. Glycobiology, 24(9):785–793, May 2014. URL: http://dx.doi.org/10.1093/glycob/cwu043, doi:10.1093/glycob/cwu043. This article has 35 citations and is from a peer-reviewed journal.](https://doi.org/10.1093/glycob/cwu043)

[7. (Ou2017Enhancement) Chenzhang Ou, Li Liu, Jiajun Wang, Siyuan Dai, Yang Qu, Ying Xiong, Wei Xi, Jiejie Xu, and Jianming Guo. Enhancement of siglec-8 expression predicts adverse prognosis in patients with clear cell renal cell carcinoma. Urologic Oncology: Seminars and Original Investigations, 35(10):607.e1-607.e8, October 2017. URL: http://dx.doi.org/10.1016/j.urolonc.2017.05.016, doi:10.1016/j.urolonc.2017.05.016. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.urolonc.2017.05.016)

[8. (Floyd2000Siglec8) Helen Floyd, Jian Ni, Ann L. Cornish, Zhizhen Zeng, Ding Liu, Kenneth C. Carter, Jane Steel, and Paul R. Crocker. Siglec-8. Journal of Biological Chemistry, 275(2):861–866, January 2000. URL: http://dx.doi.org/10.1074/jbc.275.2.861, doi:10.1074/jbc.275.2.861. This article has 161 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.275.2.861)

[9. (Nutku2003Ligation) Esra Nutku, Hideyuki Aizawa, Sherry A. Hudson, and Bruce S. Bochner. Ligation of siglec-8: a selective mechanism for induction of human eosinophil apoptosis. Blood, 101(12):5014–5020, June 2003. URL: http://dx.doi.org/10.1182/blood-2002-10-3058, doi:10.1182/blood-2002-10-3058. This article has 254 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2002-10-3058)

[10. (Yokoi2008Inhibition) Hidenori Yokoi, Oksoon H. Choi, Walter Hubbard, Hyun-Sil Lee, Brendan J. Canning, Hyun H. Lee, Seung-Duk Ryu, Stephan von Gunten, Carol A. Bickel, Sherry A. Hudson, Donald W. MacGlashan, and Bruce S. Bochner. Inhibition of fcεri-dependent mediator release and calcium flux from human mast cells by sialic acid–binding immunoglobulin-like lectin 8 engagement. Journal of Allergy and Clinical Immunology, 121(2):499-505.e1, February 2008. URL: http://dx.doi.org/10.1016/j.jaci.2007.10.004, doi:10.1016/j.jaci.2007.10.004. This article has 133 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.jaci.2007.10.004)

11. (bochner2009siglec) Bruce S Bochner. Siglec-8 on human eosinophils and mast cells, and siglec-f on murine eosinophils, are functionally related inhibitory receptors. Clinical & Experimental Allergy, 39(3):317–324, 2009. This article has 187 citations.

[12. (Bochner2005Glycan) Bruce S. Bochner, Richard A. Alvarez, Padmaja Mehta, Nicolai V. Bovin, Ola Blixt, John R. White, and Ronald L. Schnaar. Glycan array screening reveals a candidate ligand for siglec-8*. Journal of Biological Chemistry, 280(6):4307–4312, February 2005. URL: http://dx.doi.org/10.1074/JBC.M412378200, doi:10.1074/jbc.m412378200. This article has 316 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/JBC.M412378200)

[13. (Gao2010Polymorphisms) Pei-Song Gao, Kenichi Shimizu, Audrey V Grant, Nicholas Rafaels, Lin-Fu Zhou, Sherry A Hudson, Satoshi Konno, Nives Zimmermann, Maria I Araujo, Eduardo V Ponte, Alvaro A Cruz, Masaharu Nishimura, Song-Nan Su, Nobuyuki Hizawa, Terry H Beaty, Rasika A Mathias, Marc E Rothenberg, Kathleen C Barnes, and Bruce S Bochner. Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (siglec-8) gene are associated with susceptibility to asthma. European Journal of Human Genetics, 18(6):713–719, January 2010. URL: http://dx.doi.org/10.1038/ejhg.2009.239, doi:10.1038/ejhg.2009.239. This article has 52 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/ejhg.2009.239)

[14. (Sajayasbaghi2020Promoter) Mohammad Sajay-asbaghi, Mahnaz Sadeghi-shabestrai, Amir Monfaredan, Narges Seyfizadeh, Alireza Razavi, and Tohid Kazemi. Promoter region single nucleotide polymorphism of siglec-8 gene associates with susceptibility to allergic asthma. Personalized Medicine, 17(3):195–201, February 2020. URL: http://dx.doi.org/10.2217/pme-2018-0080, doi:10.2217/pme-2018-0080. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.2217/pme-2018-0080)