The RNA-binding protein HuR is required for maintenance of the germinal centre response

Ines C Osma-Garcia,Mailys Mouysset,Manuel Lebeurrier,Dunja Capitan-Sobrino,Sarah E Bell,Martin Turner,Manuel D Diaz-Muñoz

doi:10.1038/s41467-021-26908-2

Abstract

The germinal centre (GC) is required for the generation of high affinity antibodies and immunological memory. Here we show that the RNA binding protein HuR has an essential function in GC B cells to sustain the GC response. In its absence, the GC reaction and production of high-affinity antibody is severely impaired. Mechanistically, HuR affects the transcriptome qualitatively and quantitatively. The expression and splicing patterns of hundreds of genes are altered in the absence of HuR. Among these genes, HuR is required for the expression of Myc and a Myc-dependent transcriptional program that controls GC B cell proliferation and Ig somatic hypermutation. Additionally, HuR regulates the splicing and abundance of mRNAs required for entry into and transition through the S phase of the cell cycle, and it modulates a gene signature associated with DNA deamination protecting GC B cells from DNA damage and cell death.

Highlights

The germinal centre (GC) is required for the generation of high affinity antibodies and immunological memory
Immunisation of HuRfl/fl and HuRfl/fl AIDCre mice with the thymus-dependent antigen 4-hydroxy-3-nitrophenylacetyl hapten conjugated to Keyhole Limpet Hemocyanin (NP-KLH) in alum followed by analysis of NP-antigen-specific antibodies in the serum of these mice showed that human antigen R (HuR) was required for highaffinity, class-switched antibody production
This study shows the importance of the RNA-binding protein (RBP) HuR in initiating and maintaining GC responses and the production of high-affinity antibodies

Summary

Introduction

The germinal centre (GC) is required for the generation of high affinity antibodies and immunological memory. The expression and splicing patterns of hundreds of genes are altered in the absence of HuR Among these genes, HuR is required for the expression of Myc and a Myc-dependent transcriptional program that controls GC B cell proliferation and Ig somatic hypermutation. 1234567890():,; Germinal centres (GC) are the sites for active B cell proliferation and, following somatic hypermutation (SHM), selection of B cell clones with increased affinity for antigen. The scarcity of antigen makes this a highly competitive process where LZ GC B cells expressing BCRs with the highest affinities are subsequently selected for further rounds of proliferation[6] or for terminal differentiation into plasma cells or memory B cells[7]. Establishment of the GC reaction is stringently regulated by transcriptional and post-transcriptional mechanisms To achieve their functions, DZ and LZ GC B cells have very distinctive transcriptomes that reflect the differential expression of transcription factors. Post-transcriptional regulation of gene expression is an essential regulatory principle of GC responses, but it is far less well understood than the regulation by transcription factors

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Conclusion