The RNA-Binding Protein ZFP36L1 regulates the terminal differentiation of B lymphocytes

Project Information

B-different

Grant agreement ID: 841930

DOI

10.3030/841930

Project terminated on 14 December 2022

EC signature date 17 April 2019

Start date 1 January 2021

End date 2 June 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 212 933,76

EU contribution

€ 212 933,76

Coordinated by

THE BABRAHAM INSTITUTE
United Kingdom

Periodic Reporting for period 1 - B-different (The RNA-Binding Protein ZFP36L1 regulates the terminal differentiation of B lymphocytes)

Reporting period: 2021-01-01 to 2022-12-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

I discovered that ZFP36-family of RNA-binding proteins (RBP) is important to maintain germinal center (GC) responses upon influenza-A virus infection. GC B cells proliferate at a rate that is unparalleled in mammalian tissues and diversify their immunoglobulins to generate a broad range of affinities for the invading pathogen. This process is error-prone and can cause DNA damage and replication stress. I demonstrated that ZFP36-family of RBPs protect GC B cell from replication stress, by controlling cell cycle progression and survival of B cells expressing immunoglobulins with improved affinity for the invading pathogen.
In addition to this project, I generated the first paired transcriptomic and proteomic analysis of B cell maturation and differentiation to antibody-producing cells. This complementary study has enhanced our understanding of post-transcriptional regulation during B cell responses.

During my fellowship, I disseminated my research by presenting and discussing results at departmental meetings, one national meeting and one international invited seminar. I also published data in open-access scientific journals and make use of the pre-print BioRxiv sever to promptly inform the scientific community.
To facilitate data sharing and re-utilization, I made all my RNA-sequencing data freely available through Gene Expression Omnibus (GEO)-NCBI and Genialis/iMaps; whereas my proteomic data are accessible through ProteomeXchage data repository. In addition, my proteomic data are available on the Impres website (http://immpres.co.uk) a user-friendly web-interface that allows wet-lab scientists to easily navigate through complex datasets.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

My research has provided fundamental knowledge on the role of ZFP36-family of RBPs during B cell responses. My results are of wide interest for academics, as similar regulatory feedback loops may be driven by different RBPs and dominate the dynamics of gene expression in all living systems.

Graphical Abstract depicting the activity of ZFP36-family of RBPs during germinal center responses