Discovery, classification, evolution and diversity of Siglecs

Takashi Angata; Ajit Varki

doi:10.1016/j.mam.2022.101117

Discovery, classification, evolution and diversity of Siglecs

Mol Aspects Med. 2023 Apr:90:101117. doi: 10.1016/j.mam.2022.101117. Epub 2022 Aug 18.

Authors

Takashi Angata¹, Ajit Varki²

Affiliations

¹ Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan. Electronic address: angata@gate.sinica.edu.tw.
² Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: a1varki@health.ucsd.edu.

Abstract

Immunoglobulin (Ig) superfamily proteins play diverse roles in vertebrates, including regulation of cellular responses by sensing endogenous or exogenous ligands. Siglecs are a family of glycan-recognizing proteins belonging to the Ig superfamily (i.e., I-type lectins). Siglecs are expressed on various leukocyte types and are involved in diverse aspects of immunity, including the regulation of inflammatory responses, leukocyte proliferation, host-microbe interaction, and cancer immunity. Sialoadhesin/Siglec-1, CD22/Siglec-2, and myelin-associated glycoprotein/Siglec-4 were among the first to be characterized as members of the Siglec family, and along with Siglec-15, they are relatively well-conserved among tetrapods. Conversely, CD33/Siglec-3-related Siglecs (CD33rSiglecs, so named as they show high sequence similarity with CD33/Siglec-3) are encoded in a gene cluster with many interspecies variations and even intraspecies variations within some lineages such as humans. The rapid evolution of CD33rSiglecs expressed on leukocytes involved in innate immunity likely reflects the selective pressure by pathogens that interact and possibly exploit these Siglecs. Human Siglecs have several additional unique and/or polymorphic properties as compared with closely related great apes, changes possibly related to the loss of the sialic acid Neu5Gc, another distinctly human event in sialobiology. Multiple changes in human CD33rSiglecs compared to great apes include many examples of human-specific expression in non-immune cells, coinciding with human-specific diseases involving such cell types. Some Siglec gene polymorphisms have dual consequences-beneficial in a situation but detrimental in another. The association of human Siglec gene polymorphisms with several infectious and non-infectious diseases likely reflects the ongoing competition between the host and microbial pathogens.

Keywords: Evolution; Genetic polymorphism; Host-pathogen interaction; Paired receptors; Sialic acid; Siglec.

Publication types

Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Hominidae* / metabolism
Humans
Immunity, Innate / genetics
N-Acetylneuraminic Acid / metabolism
Sialic Acid Binding Ig-like Lectin 3 / genetics
Sialic Acid Binding Immunoglobulin-like Lectins* / genetics
Sialic Acid Binding Immunoglobulin-like Lectins* / metabolism

Substances

Sialic Acid Binding Immunoglobulin-like Lectins
Sialic Acid Binding Ig-like Lectin 3
N-Acetylneuraminic Acid

Grants and funding

R01 GM032373/GM/NIGMS NIH HHS/United States