B-different · The RNA-Binding Protein ZFP36L1 regulates the terminal differentiation of B lymphocytes
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-01-01 → 2023-06-02
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
The RNA-Binding Protein ZFP36L1 regulates the terminal differentiation of B lymphocytes
B cells protect us against infections by producing antibodies, which attach invading pathogens and remove them from our body. The process of antibody production must be tightly regulated to make sure that they exclusively recognize foreigner substances and that they are produced in appropriated amounts. This mainly occurs through the germinal centre, a microenvironment where B cells improve their ability to recognize and attach the invading pathogen and proliferate. When the germinal centre is not well controlled, dysfunctional B cells can cause defective immunity, autoimmunity, or B-cell lymphomas. The aim of my project was to elucidate new mechanisms that regulate germinal centre B cell responses and antibody production. In particular, I studied the role of two RNA-biding proteins and found that they protect germinal centre B cells from replication stress by controlling their proliferation and survival. Because these RNA-binding proteins might play a role in pathological processes, enhancing our understanding of their function may lead to new opportunities for drug discovery.
Data: CORDIS, © European Union
Project objective
Plasma cells (PC) secreting high-affinity antibodies are key for long-term immunity and the success of vaccines. PC are mainly generated within the germinal centre (GC), a microenvironment where B cells undergo affinity maturation and selection. The GC reaction guarantees that only B cells expressing immunoglobulin with the highest affinity for the antigen will commit to terminal differentiation. Stringent regulation is essential, as dysfunctional GC B cells can cause defective immunity, autoimmunity, or B-cell lymphomas.Affinity maturation requires rapid changes in the B cell transcriptome and proteome to enable cell fate decisions. This is governed by the interplay of signal transduction pathways and regulation at transcriptional and post-transcriptional levels. Post-transcriptional control is key for rapid remodelling of gene expression, yet its role in terminal differentiation remains largely unexplored. The host lab pioneers the study of RNA-binding proteins (RBP) in lymphocyte development and has unpublished data indicating that the RBP ZFP36L1 inhibits terminal differentiation of B cells in vitro. The regulation and function of ZFP36L1 in GCs is however unknown.In this proposal I will build on the unique and multidisciplinary expertise of the host lab and my experience on post-transcriptional regulation and immunity to address how ZFP36L1 dictates fate decision of B cells. Uniquely available mouse models will allow me to study how signal strength and signal transduction control ZFP36L1 activity and its downstream implications for humoral immunity. Cutting-edge technologies will be employed to elucidate the dynamics of ZFP36L1-RNA interactions and how they in turn define the proteome and fate of GC B cells.This work will reveal the role of an important new regulator of PC differentiation, and will enable me to expand my knowledge, acquire new biochemical, bioinformatics and managerial skills, and facilitate my career development as an independent scientist.
Original text from CORDIS.
Participants
- THE BABRAHAM INSTITUTE · CambridgeCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union