Faulty genome decoding knocks down B cell ability to produce antibodies

Faulty genome decoding knocks down B cell ability to produce antibodies

A multinational, multidisciplinary team led by researchers from the Babraham Institute have made important advances in understanding how a protein involved in the processing of genetic information is crucial for the survival of B cells and the ability to produce antibodies, an important part of the body’s response to infection. The research is published online in Nature Immunology and is a new discovery of an essential function for a sequence-specific RNA-binding protein in B cells.
The protein, known as HuR, is an RNA-binding protein and the research looked at the role of HuR in B cells, the cells of our immune system that produce antibodies in response to infection.
RNA binding proteins bind to RNA as it is produced and they regulate the RNA’s maturation, cellular location and stability. For RNA transcripts that encode proteins, the immature transcripts contain sections to be copied into the protein (exons), and sections (introns) which should not be copied but removed from the sequence to make a mature messenger RNA transcript from which to make a protein. In this function, the RNA binding proteins are the cell’s editors, editing out the RNA sections that should not be used to make the protein. This process is called splicing.
The research published today innovatively combined three different technologies: measuring RNA abundance, mRNA translation and direct measurements of HuR–RNA interactions at the single nucleotide level to analyse the B cell transcriptome - the sum total of RNA transcripts present in B cells. This approach allowed the researchers to identify the RNA targets of HuR and pinpoint the exact binding sites of HuR in the transcripts.
The analysis of the target RNAs bound by HuR uncovered that the HuR controls the splicing and production of proteins with roles in the cell’s metabolism and energy balance. Triggering of the immune system leads to a metabolic boost in B cells to enable the production of antibodies to fight the infection. HuR deficient cells were unable to meet the metabolic demands required to fuel the proliferation of B cells following activation of an immune response or manage the accumulation of toxic reactive oxygen species as a metabolic by-product.
Manuel Diaz-Muñoz, a postdoctoral researcher at the Babraham Institute and lead author on the paper said: “This research looks at a fundamental, quality control mechanism of genome regulation. Without HuR and correct post-transcriptional processing of messenger RNA, the B cells cannot coordinate the increase in metabolism needed to proliferate and to produce antibodies as a response to infection.”
This research is part of the Babraham Institute’s research programme focusing on understanding the processes that regulate the development, survival and function of white blood cells. Understanding these processes is crucial in order to combat autoimmune diseases, support healthy ageing, improve vaccines, develop tumour immunotherapy and improve the efficiency of organ transplantation. This work was funded by the Biotechnology and Biological Science Research Council (BBSRC).

Image description:

The image above shows the cellular location of HuR protein (red) and mRNA processing bodies (green) in B cells after activation. The nucleus is shown in blue.

Animal research statement:

As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here involved the generation of mice with a conditional, B-cell-specific deletion of Elavl1, the gene that encodes HuR and the use of control mice as comparison. The mice were used to provide tissues to analyse HuR expression, and B cell and antibody counts, and immunised to investigate the requirement of HuR in the generation of antibodies. 
Please follow the link for further details of our animal research, how we use alternatives whenever possible and our animal welfare practices.

Publication reference:

Diaz-Muñoz et al. (2014). The RNA-binding protein HuR is essential for the B cell antibody response. Nature Immunology.

Associated researchers (in author order):

Manuel Diaz-Muñoz, postdoc researcher (Turner lab)
Kirsten Fairfax, visiting fellow (Turner lab). University of Melbourne, Australia
Martin Turner, group leader, Lymphocyte Signalling & Development programme