Genetic regulation of post-translational modification of two distinct proteins

Landini, Arianna; Trbojević‐Akmačić, Irena; Navarro, Pau; Tsepilov, Yakov A.; Sharapov, Sodbo; Vučković, Frano; Polašek, Ozren; Hayward, Caroline; Petrović, Tea; Vilaj, Marija; Aulchenko, Yurii S.; Lauc, Gordan; Wilson, James F.; Klarić, Lucija

doi:10.1038/s41467-022-29189-5

Cited by 26 publications

(33 citation statements)

References 72 publications

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“…Several gene array analyses correlating IgG N-glycan traits with genome-wide polymorphic variants have allowed to identify gene pathways involved in N-glycome regulation, several of which were confirmed in more than one study (134)(135)(136)(137)(138)(139)(140). Some of the genes identified are glycosyltransferases, most significantly FUT8, B4GALT1 and MGAT3 (the latter encoding the GnTIII enzyme)(Figure 2), as well as transcription factors known or suspected to regulate these genes, such as RUNX1, RUNX3, IKZ1, IKZ3, IRF1, SMARCB1, TBX21O and HFN1 (138).…”

Section: Modulation Of Igg Fucosylation In Physiological States and D...mentioning

confidence: 93%

Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

2022

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The presence of fucose on IgG1 Asn-297 N-linked glycan is the modification of the human IgG1 Fc structure with the most significant impact on FcɣRIII affinity. It also significantly enhances the efficacy of antibody dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells in vitro, induced by IgG1 therapeutic monoclonal antibodies (mAbs). The effect of afucosylation on ADCC or antibody dependent phagocytosis (ADCP) mediated by macrophages or polymorphonuclear neutrophils (PMN) is less clear. Evidence for enhanced efficacy of afucosylated therapeutic mAbs in vivo has also been reported. This has led to the development of several therapeutic antibodies with low Fc core fucose to treat cancer and inflammatory diseases, seven of which have already been approved for clinical use. More recently, the regulation of IgG Fc core fucosylation has been shown to take place naturally during the B-cell immune response: A decrease in α-1,6 fucose has been observed in polyclonal, antigen-specific IgG1 antibodies which are generated during alloimmunization of pregnant women by fetal erythrocyte or platelet antigens and following infection by some enveloped viruses and parasites. Low IgG1 Fc core fucose on antigen-specific polyclonal IgG1 has been linked to disease severity in several cases, such as SARS-CoV 2 and Dengue virus infection and during alloimmunization, highlighting the in vivo significance of this phenomenon. This review aims to summarize the current knowledge about human IgG1 Fc core fucosylation and its regulation and function in vivo, in the context of both therapeutic antibodies and the natural immune response. The parallels in these two areas are informative about the mechanisms and in vivo effects of Fc core fucosylation, and may allow to further exploit the desired properties of this modification in different clinical contexts.

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Section: Modulation Of Igg Fucosylation In Physiological States and D...mentioning

confidence: 93%

Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

2022

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“…These networks seem to be protein and/or cell-type specific, as indicated by the recent comparison of genes that regulate IgG and Tf glycosylation. 325…”

Section: Ht-glycomics In Genetic Studiesmentioning

confidence: 99%

“…Generally, GWAS studies indicated that regulatory networks that govern protein glycosylation include many other genes in addition to enzymes that are directly involved. These networks seem to be protein and/or cell-type specific, as indicated by the recent comparison of genes that regulate IgG and Tf glycosylation …”

Section: Applicationsmentioning

confidence: 99%

High-Throughput Glycomic Methods

et al. 2022

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Glycomics aims to identify the structure and function of the glycome, the complete set of oligosaccharides (glycans), produced in a given cell or organism, as well as to identify genes and other factors that govern glycosylation. This challenging endeavor requires highly robust, sensitive, and potentially automatable analytical technologies for the analysis of hundreds or thousands of glycomes in a timely manner (termed high-throughput glycomics). This review provides a historic overview as well as highlights recent developments and challenges of glycomic profiling by the most prominent high-throughput glycomic approaches, with N-glycosylation analysis as the focal point. It describes the current state-of-the-art regarding levels of characterization and most widely used technologies, selected applications of high-throughput glycomics in deciphering glycosylation process in healthy and disease states, as well as future perspectives.

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“…Most gene-aggregated rare variants were associated with protein-specific glycans (transferrin: variants in FUT6, TIRAP, MSR1 and FOXI1 genes, IgG: variants in MGAT3, ST6GAL1 and RFXAP genes); only FUT8 was associated with glycans from both proteins (Table 2, Supplementary Tables 1 and 2). Almost all identified genes encode key enzymes in protein glycosylation (MGAT3, ST6GAL1, FUT6, FUT8) or have been previously associated with transferrin and IgG glycan traits in GWAS analysis (MSR1, FOXI1) 17,18 . The exceptions are TIRAP and RFXAP, which have no previously known link to protein glycosylation.…”

Section: Exome Variant Annotation 96mentioning

confidence: 99%

“…All studies published to date exploring the genetic regulation of total plasma protein, immunoglobulin G (IgG) and transferrin N-glycosylation have employed single variant-based GWAS tests, mostly uncovering common variants located in non-coding regions of the genome [16][17][18][19][20][21][22][23] . Rare variants contributing to glycan variation, and their impact on human health, thus remain unexplored.…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing reveals aggregates of rare variants in glycosyltransferase and other genes influencing immunoglobulin G and transferrin glycosylation

Landini

Timmers

Frkatović

et al. 2022

Preprint

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It is often difficult to be certain which genes underlie the effects seen in association studies. However, variants that disrupt the protein, such as predicted loss of function (pLoF) and missense variants, provide a shortcut to identify genes with a clear biological link to the phenotype of interest. Glycosylation is one of the most common post-translationalmodifications of proteins, and an important biomarker of both disease and its progression. Here, we utilised the power of genetic isolates, gene-based aggregation tests and intermediate phenotypes to assess the effect of rare (MAF<5%) pLoF and missense variants from whole exome sequencing on the N-glycome of plasma transferrin (N=1907) and immunoglobulin G (N=4912), and their effect on diseases. We identified significant gene-based associations for transferrin glycosylation at 5 genes (p<8.06x10-8) and for IgG glycan traits at 4 genes (p<1.19x10-7). Associations in three of these genes (FUT8, MGAT3 and RFXAP) are driven by multiple rare variants simultaneously contributing to protein glycosylation. Association at ST6GAL1, with a 300-fold up-drifted variant in the Orkney Islands, was detectable by a single-point exome-wide association analysis. Glycome-associated aggregate associations are located in genes already known to have a biological link to protein glycosylation (FUT6, FUT8 for transferrin; FUT8, MGAT3 and ST6GAL1 for IgG) but also in genes which have not been previously reported (e.g. RFXAP for IgG). To assess the potential impact of rare variants associated with glycosylation on other traits, we queried public repositories of gene-based tests, discovering a potential connection between transferrin glycosylation, MSR1, galectin-3, insulin-like growth factor 1 and diabetes. However, the exact mechanism behind these connections requires further elucidation.

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Genetic regulation of post-translational modification of two distinct proteins

Cited by 26 publications

References 72 publications

Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

High-Throughput Glycomic Methods

Exome sequencing reveals aggregates of rare variants in glycosyltransferase and other genes influencing immunoglobulin G and transferrin glycosylation

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