Abstract
Sialic acids, a group of acidic sugars abundantly expressed in the tissues of deuterostome animals but rarely found in microbes, serve as a “signature of self” for these animals. Cognate sensors for sialic acids include Siglecs, a family of transmembrane lectins of vertebrate immune systems that recognize glycans containing sialic acids. A type of sialic acid called N-glycolylneuraminic acid (Neu5Gc) is abundant in many mammalian lineages including great apes, the closest extant relatives of modern human, but was lost in the lineage leading to modern human via the pseudogenization of the CMAH gene encoding the enzyme that converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc. Loss of Neu5Gc appears to have influenced the evolution of human Siglecs, such as the adjustment of sialic acid binding preferences and the inactivation of at least one Siglec. In addition, various mechanistic studies using model systems and genetic association studies have revealed that some human Siglecs interact with pathogens and influence the outcome of infections, and these pathogens in turn likely influence the evolution of these Siglecs. By understanding the evolutionary forces affecting Siglecs, we shall achieve a better appreciation of Siglec functions, and by understanding Siglec functions, we can obtain deeper insight into the evolutionary processes driving Siglec evolution.
Highlights
The role of immunity is to distinguish self vs. non-self and to eliminate or contain the latter
Rodents are essential model animals for mechanistic studies in immunology, differences in primate and rodent CD33-related Siglecs [15] impose a significant challenge in the extrapolation of findings in rodents to human immunology. This situation parallels that of other immunoglobulin-like receptor families, leukocyte immunoglobulin-like receptors (LILR) and killer cell immunoglobulin-like receptors (KIR), that are encoded in a gene cluster on the same human chromosomal region as CD33-related Siglecs and are involved in self-recognition through interaction with MHC class I [19,20,21]
Some bacteria have developed ways to synthesize Neu5Ac, so far no study has demonstrated the presence of Neu5Gc on microbes [27] [A recent genomic survey [28] reported the presence of CMAHlike sequences in several microbial genomes, including those of several Helicobacter species that may express sialic acids
Summary
The role of immunity is to distinguish self vs. non-self (or what is not dangerous vs. dangerous) and to eliminate or contain the latter. Most of the known mammalian Siglecs are expressed on leukocytes and have an intracellular sequence motif called the immunoreceptor tyrosine-based inhibitory motif (ITIM) that recruits tyrosine phosphatase SHP-1 and transduces inhibitory signals They are considered to function as sensors for sialic acids as a molecular signature of self. Some bacteria have developed ways to synthesize Neu5Ac, so far no study has demonstrated the presence of Neu5Gc on microbes [27] [A recent genomic survey [28] reported the presence of CMAHlike sequences in several microbial genomes, including those of several Helicobacter species that may express sialic acids Their enzymatic function has not yet been investigated]. Possible explanations for this fact may include: [1] the adaptation of human Siglecs
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