Evolutionary forces shaping the Golgi glycosylation machinery: why cell surface glycans are universal to living cells

Abstract

Despite more than 3 billion years since the origin of life on earth, the powerful forces of biological evolution seem to have failed to generate any living cell that is devoid of a dense and complex array of cell surface glycans. Thus, cell surface glycans seem to be as essential for life as having a DNA genetic code, diverse RNAs, structural/functional proteins, lipid-based membranes, and metabolites that mediate energy flux and signaling. The likely reasons for this apparently universal law of biology are considered here, and include the fact that glycans have the greatest potential for generating diversity, and thus evading recognition by pathogens. This may also explain why in striking contrast to the genetic code, glycans show widely divergent patterns between taxa. On the other hand, glycans have also been coopted for myriad intrinsic functions, which can vary in their importance for organismal survival. In keeping with these considerations, a significant percentage of the genes in the typical genome are dedicated to the generation and/or turnover of glycans. Among eukaryotes, the Golgi is the subcellular organelle that serves to generate much of the diversity of cell surface glycans, carrying out various glycan modifications of glycoconjugates that transit through the Golgi, en route to the cell surface or extracellular destinations. Here I present an overview of general considerations regarding the selective forces shaping evolution of the Golgi glycosylation machinery, and then briefly discuss the common types of variations seen in each major class of glycans, finally focusing on sialic acids as an extreme example of evolutionary glycan diversity generated by the Golgi. Future studies need to address both the phylogenetic diversity the Golgi and the molecular mechanisms for its rapid responses to intrinsic and environmental stimuli.

Figure 1.

Universal characteristics of all living cells. As indicated in the figure and discussed in the text, cell surface glycosylation is among the key features that are universal to all living cells. However, in contrast to the genetic code, the degree of evolutionary conservation of glycans between taxa is the least. The likely reasons for this difference are discussed in the text. In eukaryotes, most of the resulting structural diversity of cell surface glycosylation is generated by the Golgi apparatus.

Figure 2.

An example of the thickness of the cell surface glycocalyx. Shown is an electron microscopic overview of a rat left ventricular myocardial capillary stained with Alcian blue 8GX. Alcian Blue will react with acidic glycans such as glycosaminoglycans and sialic acids, as well as the nonGolgi derived glycan hyaluronan (bar = 1 µm). It can be seen that the glycocalyx on the luminal surface of the vessel wall is almost as thick as the underlying endothelial cell, which synthesizes it (Used with permission from van den Berg et al. 2003).

Figure 3.

Forces driving the evolutionary diversification of glycans. Each arrowed circle represents a potential vicious cycle, driven by a “Red Queen” effect, in which hosts are constantly trying to evade the more rapidly evolving pathogens that infect them. Hosts require glycans for critical cellular functions but must constantly change them to evade glycan-binding pathogens, yet without impairing their own survival. Hosts also produce soluble glycans such as mucins, which act as decoys to divert pathogens from cell surfaces; but pathogens are constantly adjusting to these defenses. Hosts recognize pathogen-specific glycans as markers of “non-self,” but pathogens can modify their glycans to more closely mimic host glycans. There are also possible secondary Red Queen effects involving host glycan binding proteins that recognize “self.” In each of these cycles, hosts with altered glycans that can still carry out adequate cellular functions are most likely to survive. (Modified with permission from Varki [2006].)

Figure 4.

Common classes of animal glycans. The major classes of animal glycans are shown, with an emphasis on typical vertebrate sugar chains. The shaded blue boxes indicate the core glycan sequences that are conserved in most or all taxa that express such glycan classes. The monosaccharide abbreviations are GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; Gal, Galactose; Glc, Glucose; Man, Mannose; Fuc, Fucose; Xyl, Xylose; GlcA, Glucuronic acid; and, IdoA, Iduronic acid. (Reproduced with permission from Varki and Sharon [2009].)

Figure 5.

Dominant pathways of N-glycan processing in various taxa. See text for further discussion. Monosaccharide abbreviations are as in Figure 4. (Reproduced with permission from Varki et al. [2009b].)

Figure 6.

Diversity in the sialic acids. All known sialic acids have a common nine-carbon backbone attached in the α configuration to the underlying sugar chain (Varki and Schauer 2009). The sialome can be analyzed at the following complexity levels: (A) Sia core and core modifications: esterification (with various groups), o-methylation, lactonization or lactamization yielding >50 different structures, (B) Linkage to the underlying sugar (three major and many minor linkages), (C) Identity and arrangement of the underlying sugars that can also be further modified by fucosylation or sulfation, (D) Glycan class (N-linked, O-linked or glycosphingolipids), (E) Spatial organization of the Sia in sialylated microdomains (including glycosynapses and clustered saccharide patches), and higher levels of the cellular and organismal milieu. Sia, Sialic acid; other monosaccharide abbreviations are as in Figure 4. (Reproduced with permission from Cohen and Varki [2010].)