The Role of N-glycosylation in BCRs of Different Classes and in Precursor-BCRs

N-linked glycans are carbohydrates that are attached to multiple proteins that pass the secretory pathway and have an impact on e.g. protein stability and function. Similar to secreted antibodies, B cell receptors (BCRs) and their precursors are highly glycosylated. In this project, we aim at elucidating the impact of N-glycosylation on the function of BCRs at different developmental stages, of BCRs of different subtypes, and of BCRs from different lymphomas. We were able to show that the function of the precursor-BCR (pre-BCR) is strictly dependent on the presence of an N-linked glycan in the µ-heavy chain constant region 1, where it promotes self-ligation between pre-BCRs on the very same cell.  Self-ligation then leads to cell-autonomous signalling, proliferation and further development of the lymphocyte (Figure 2). During B cell development, the subtype of the heavy chain (HC) of BCRs changes from a state where only the µ-type is expressed to a state where the µ-type is expressed together with HCs of the d-type. Since the variable region, important for antigen recognition remains the same, the reason for this is still poorly understood.

We are interested in how signalling from BCRs with HCs of the µ- and d-type differs depending on the particular subtype and are studying the structural basis and functional consequences of these differences. Here, we focus on differential glycosylation, which we study e.g. by using a panel of glycan-binding proteins called lectins. Interestingly, the glycosylation pattern of BCRs derived from diseased B lymphocytes differs from that of healthy B cells. It has been shown that, for instance, in BCRs from Follicular Lymphomas, additional N-glycosylation sites are frequently introduced during the process of somatic hypermutation. In this part of the project, we seek to find out whether and how these changes in glycosylation influence BCR signalling and may contribute to the onset and/or progression of the disease.