Core fucosylation within the Fc-FcγR degradation pathway promotes enhanced IgG levels via exogenous L-fucose.

α1,6-Fucosyltransferase (Fut8) is the enzyme responsible for catalyzing core fucosylation. Exogenous L-fucose upregulates fucosylation levels through the GDP-fucose salvage pathway. This study investigated the relationship between core fucosylation and immunoglobulin G (IgG) amounts in serum utilizing WT (Fut8+/+), Fut8 heterozygous knockout (Fut8+/-), and Fut8 knockout (Fut8-/-) mice. The IgG levels in serum were lower in Fut8+/- and Fut8-/- mice compared with Fut8+/+ mice. Exogenous L-fucose increased IgG levels in Fut8+/- mice, while the ratios of core fucosylated IgG versus total IgG showed no significant difference among Fut8+/+, Fut8+/-, and Fut8+/- mice treated with L-fucose. These ratios were determined by Western blot, lectin blot, and mass spectrometry analysis. Real-time PCR results demonstrated that mRNA levels of IgG Fc and neonatal Fc receptor, responsible for protecting IgG turnover, were similar among Fut8+/+, Fut8+/-, and Fut8+/- mice treated with L-fucose. In contrast, the expression levels of Fc-gamma receptor Ⅳ (FcγRⅣ), mainly expressed on macrophages and neutrophils, were increased in Fut8+/- mice compared to Fut8+/+ mice. The effect was reversed by administrating L-fucose, suggesting that core fucosylation primarily regulates the IgG levels through the Fc-FcγRⅣ degradation pathway. Consistently, IgG internalization and transcytosis were suppressed in FcγRⅣ-knockout cells while enhanced in Fut8-knockout cells. Furthermore, we assessed the expression levels of specific antibodies against ovalbumin and found they were downregulated in Fut8+/- mice, with potential recovery observed with L-fucose administration. These findings confirm that core fucosylation plays a vital role in regulating IgG levels in serum, which may provide insights into a novel mechanism in adaptive immune regulation.

An emerging role of N-glycosylation in cancer chemoresistance.

Chemoresistance poses a significant obstacle in the effective treatment of cancer, limiting the success of chemotherapy regimens. N-glycosylation, the most important post-translational modification (PTM), plays multifaceted roles in the intricate landscape of cancer progression, particularly drug resistance in cancer cells. This review explores the complex relationship between N-glycosylation and chemoresistance in cancer. Altered glycosylation patterns have been proven to impact drug efflux mechanisms in cancer cells, which can further influence the intracellular concentration of chemotherapy drugs. Moreover, N-glycosylation also plays a regulatory role in cell signaling pathways and apoptosis regulators, continuously affecting the stemness and survival of cancer cells under the selective pressure of chemotherapy. Additionally, the impact of the tumor microenvironment on glycosylation patterns adds complexity to this interplay. This review discusses current research findings, challenges, and future directions based on the roles of N-glycosylation in cancer chemoresistance, emphasizing the potential for targeted therapeutic interventions to enhance the effectiveness of chemotherapy and improve patient outcomes.