Same role but different actors: genetic regulation of post-translational modification of two distinct proteins

Abstract

Post-translational modifications (PTMs) diversify protein functions and dynamically coordinate their signalling networks, influencing most aspects of cell physiology. Nevertheless, their genetic regulation or influence on complex traits is not fully understood. Here, we compare for the first time the genetic regulation of the same PTM of two proteins – glycosylation of transferrin and immunoglobulin G (IgG). By performing genome-wide association analysis of transferrin glycosylation, we identified 10 significantly associated loci, all novel. Comparing these with IgG glycosylation-associated genes, we note protein-specific associations with genes encoding glycosylation enzymes (transferrin - MGAT5, ST3GAL4, B3GAT1; IgG - MGAT3, ST6GAL1) as well as shared associations (FUT6, FUT8). Colocalisation analyses of the latter suggest that different causal variants in the FUT genes regulate fucosylation of the two proteins. We propose that they affect the binding of different transcription factors in different tissues, with fucosylation of IgG being regulated by IKZF1 in B-cells and of transferrin by HNF1A in liver.

Developments and perspectives in high-throughput protein glycomics: enabling the analysis of thousands of samples

“…Other opportunities in monoclonal antibody drug development lay in targeting carbohydrate-based antigens. However, knowledge about the regulation of glycosylation is still rudimentary and large glycomics studies will be needed to understand the regulation of glycosylation and its tissue-specific differences ( Hakomori 2002 ; Landini et al. 2021 ).…”