Epigenetic regulation of glycosylation could be a mechanism used by complex organisms to compete with microbes on an evolutionary scale
Introduction
Glycosylation is the most diverse post-translational protein modification. Hundreds of specific enzymes are involved in the synthesis of complex oligosaccharide structures (glycans) that are covalently bound to protein backbones [1]. Some of these enzymes are very specific and contribute to the synthesis of a limited number of structures on a small number of proteins, while others (like ER-glycosyltransferases involved in the synthesis of N-glycans) affect thousands of different proteins. This process is not template driven and thus results in a huge complexity of glycoproteome, estimated to be several orders of magnitude larger than proteome [2]. The intricate mechanisms by which the interplay of gene expression and intracellular localization of their products give rise to specific glycan structures is only starting to be understood [3].
N-glycosylation is essential for multicellular life and its complete absence is embryonically lethal [4]. Genetic defects that affect protein glycosylation are relevant to human health and cause up to 30 described human diseases [2], [5]. It was recently predicted that a surprisingly high share of all known disease-causing missense mutations result in gains of glycosylation [6], [7]. On the other hand, terminal variability in glycans is common (e.g., ABO blood groups) and contribute to the protein heterogeneity in a population that can be advantageous for evading pathogens and adapting to changing environment [8]. Due to experimental limitations in quantifying glycans in complex biological samples, the knowledge about genetic polymorphisms and complex genetics of glycosylation that quantitatively affect levels of individual glycans is still very limited [2]. However, the fact that almost all membrane and extracellular proteins in higher eukaryotic organisms are glycoproteins reflects the importance of this feature [9].
Glycosylation is the only post-translational modification that can produce significant structural parts of proteins. However, contrary to the polypeptide backbone, glycan parts of glycoproteins are not directly encoded in genes. Instead of being molded by a single gene, glycan structures are encoded in a network of hundreds of glycosyltransferases, glycosidases, transporters, transcription factors and other proteins.
Section snippets
The hypothesis
Basic structural features of glycosylation were invented by archeabacteria, but glycans acquired their full functional complexity only in higher eukaryotes [10]. This invention occurred in parallel with the appearance of multicellular life, and even though it is too speculative to say that the invention of glycosylation enabled appearance of multicellular life, the fact that nearly all proteins that were invented after the appearance of multicellular organisms are glycosylated, clearly
Structural and functional aspects of protein glycosylation
A typical glycan is a branched molecule containing between 10 and 15 monosaccharides linked in a rather complex manner. Depending on the structure of a glycan and protein to which it is attached, glycans can have many different functions: they are important in proper folding of proteins; they regulate function of protein backbones by differential processing of glycosylation [11]; they can be strategically placed so that they can provide protease protection without interfering with the function
Variability and heritability of glycans
Cells of higher eukaryotes are covered with a dense layer of glycoconjugates (glycocalyx) that mediate their communication with the outside world. When pathogens seek the access to the interior of the cell they first have to bind to some of the glycoconjugates on the cell surface, thus the variability of glycan structures represents a valuable tool that higher eukaryotes use to outmaneuver rapidly evolving pathogens. In spite of differences in genealogy and biosynthetic mechanisms of
Epigenetic regulation of gene expression
Term ‘epigenetic’ was coined to refer the changes which occur ‘above the gene(tics)’, i.e. to changes in gene expression without a change in the DNA sequence. Epigenetic genome modification is a complex network of DNA methylation, post-translational modifications of histone proteins, RNA interference (RNAi), action of non-coding RNAs and mechanisms that control the higher-level chromatin organization [27]. Environmental influences (such as nutrition, exposure to pharmacological agents and
Significance and experimental verification of the hypothesis
Large structural variability provided by glycans apparently represents a significant evolutionary advantage since nearly all proteins invented after the appearance of multicellular life are glycosylated. By modifying gene expression, intracellular localization and activity of enzymes that synthesize glycans, complex organisms could develop novel structural features without introducing probably deleterious changes in their genome. If epigenetic marks in these genes could be used to transmit
Acknowledgement
This work is supported by Grants #309-0061194-2023 (to G.L.), and #119-1191196-1224 (to V.Z.) from the Croatian Ministry of Science, Education and Sport.
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