Core Fucosylation Regulates the Function of Pre-BCR, BCR and IgG in Humoral Immunity

Abstract

Most of the membrane molecules involved in immune response are glycosylated. N-glycans linked to asparagine (Asn) of immune molecules contribute to the protein conformation, surface expression, stability, and antigenicity. Core fucosylation catalyzed by core fucosyltransferase (FUT8) is the most common post-translational modification. Core fucosylation is essential for evoking a proper immune response, which this review aims to communicate. First, FUT8 deficiency suppressed the interaction between μHC and λ5 during pre-BCR assembly is given. Second, we described the effects of core fucosylation in B cell signal transduction via BCR. Third, we investigated the role of core fucosylation in the interaction between helper T (T_H) cells and B cells. Finally, we showed the role of FUT8 on the biological function of IgG. In this review, we discussed recent insights into the sites where core fucosylation is critical for humoral immune responses.

Keywords: BCR; IgG; core fucosylation; humoral immune response; pre-B cell.

Figure 1

Glycosyltransferases involving in the biosynthesis of branching N-glycans. α2,6 sialyltransferases (ST6) and/or α2,3 sialyltransferases (ST3) that act on galactose, β1,4 galactosyltransferases (β1,4GalT) and/or β1,3 galactosyltransferases (β1,3GalT) that act on N-acetylglucosamine (GlcNAc), and the family of N-acetylglucosamine transferases (GnT-I, GnT-II, GnT-III, GnT-IV, GnT-V and so on) that participate in GlcNAc synthesis. Fucosyltransferases (FUT3, FUT4, FUT5, FUT6, FUT7, FUT8, FUT9) can attach fucose in either α1,3/α1,4 or α1,6 linkage. These enzymes act sequentially, so that the product of one enzyme yields a preferred acceptor substrate for the subsequent action of another. Different proteins may have different subsets of N-glycans, which is referred to as microheterogeneity. All N-glycans share a common core sugar sequence, Manα1–6(Manα1–3) Manβ1–4GlcNAcβ1–4GlcNAcβ1.

Figure 2

Core fucosylation modification in mammalian N-glycans is catalyzed by FUT8. The ER-Golgi pathway harbors many glycan-modifying enzymes in eukaryotic cells. The glycosyltransferases that operate in the ER are woven into the ER membrane. In contrast, the glycosyltransferases in Golgi compartments are generally type II membrane proteins with a small cytoplasmic amino-terminal domain, a single transmembrane domain, and a large lumenal domain that has an elongated stem region and a globular catalytic domain. FUT8 is a typical type II membrane protein and a Golgi apparatus–resident glycosyltransferase to catalyze the transfer of a fucose from GDP-fucose to the inner GlcNAc of N-glycans through α1,6-linkage (core fucosylation). There are two different pathways for producing GDP-fucose, namely salvage pathway and de novo pathway. The GDP-fucose is transferred from the cytosol into the Golgi apparatus by GDP-fucose transporter (GFT). The sugar additions, such as galactosylation by GalT, fucosylation by FUTs and sialylation by STs, mostly occurring in the trans-Golgi.

Figure 3

Core fucosylation regulates the assembly of pre-BCR. The early B cells growth depends on the assembly of pre-BCR. The conserved N⁴⁶-glycosylation site on C_H1 domain of μHC played a critical role in modulation of the interaction of μHC and λ5 before the formation of pre-BCR. Removal of core fucose of μHC impaired the interaction between μHC and λ5, and pre-BCR assembly, which is necessary and sufficient for signal transduction via pre-BCR and early B cell proliferation.

Figure 4

Core fucosylation regulates the signal transduction via BCR. Upon Ag engagement, BCRs on the surface of B cells associated with lipid rafts and triggers signal transductions required for the activation of B cells. Core fucosylation promoted B cells to form a highly efficient lipid raft domain, thereby regulating signal transduction via BCR.

Figure 5

De-fucosylated IgG-Fc domain enhanced the induction of ADCC. ADCC is a specific effector mechanism of natural killer (NK) cells. ADCC refers to the killing of a target cell, which is coated with Abs by NK cells of the immune system. When the antibodies bind to the target Ag (tumor Ag), the IgG Fc is recognized by NK cells via FcγRs on their surfaces. Following recognition, the NK cells release chemicals, which then lyse and kill the target cell bound to the Ab. The removal of core fucosylation at Asn²⁹⁷ on IgG₁ results in a 50~100-fold enhancement of ADCC.