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

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.

NK cell expansion requires HuR and mediates control of solid tumors and long-term virus infection

“…We did not observe differences in cytokine production, even under conditions that are tightly regulated by transcription and translation ( Piersma et al, 2019 ), potentially because NK cells do not require helper differentiation as CD4 + T cells do. In B cells, HuR was found to be essential for the B cell antibody and germinal center responses ( Osma-Garcia et al, 2021 ; Diaz-Muñoz et al, 2015 ). LPS-stimulated B cells require HuR for metabolic fitness including alternative splicing of dlst ( Diaz-Muñoz et al, 2015 ), which was not detected in germinal center B cells ( Osma-Garcia et al, 2021 ).…”

“…In mature myeloid cells, HuR represses proinflammatory cytokine production and protects against LPS-induced endotoxemia ( Yiakouvaki et al, 2012 ). B cells require HuR for metabolic fitness, which is required for an optimal antibody response ( Diaz-Muñoz et al, 2015 ), while HuR is required for germinal center B cell maintenance and somatic hypermutation ( Osma-Garcia et al, 2021 ). HuR negatively affects T cell maturation, deletion, and egress in thymocytes ( Papadaki et al, 2009 ), whereas in mature CD4 + T cells, HuR affects cytokine production ( Gubin et al, 2014 ).…”

Immunomodulation—a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system

“…The well-established transcription factors involved in B-cell maturation, differentiation, and maintenance are as follows: Bcl ( 49 ); E2A, PAX5, and FOXO1 ( 50 ); NF-κB ( 51 – 53 ); and Myc ( 54 , 55 ). Recently, microRNAs ( 56 , 57 ), RNA-binding proteins ( 58 ), and transcriptional enzymes ( 59 ) have attracted much attention as potential targets to regulate B-cell functioning ( 60 ) ( Figure 2 ).…”

Regulation of the Alternative Neural Transcriptome by ELAV/Hu RNA Binding Proteins

“…HuR is ubiquitously expressed across different tissues, while HuB/C/D are largely restricted to the nervous system, and sometimes referred as nELAVL proteins (King et al, 1994;Akamatsu et al, 1999). Mouse HuR knockouts are embryonic lethal (Ghosh et al, 2009;Katsanou et al, 2009), and conditional analyses reveal roles across a wide range of biological settings, including but certainly not limited to angiogenesis (Chang et al, 2014), germinal centre response (Osma-Garcia et al, 2021), adipogenesis (Siang et al, 2020), and colon cancer (Akaike et al, 2014). In contrast, mutants of neural ELAV/Hu paralogs such as HuC (Ince-Dunn et al, 2012) and HuD (Akamatsu et al, 2005) There are additional important, but not well-appreciated, features of the ELAV/Hu phylogeny, even though they were described some time ago (Samson, 2008).…”

“…As ELAV/Hu studies have moved into the genomic age, it became de rigueur to use RNA-seq for comprehensive documentation of effects on alternative splicing ( Figure 3A ). Indeed, broad splicing changes are observed upon manipulation of ELAV/Hu factors, including with HuR ( Akaike et al, 2014 ; Chang et al, 2014 ; Osma-Garcia et al, 2021 ; Sena et al, 2021 ) and neural ELAV members ( Ince-Dunn et al, 2012 ; Berto et al, 2016 ; Scheckel et al, 2016 ; Bowles et al, 2021 ). At least a portion of these may be direct targets, as supported by corresponding evidence of ELAV/Hu occupancy on flanking intron regions ( Lebedeva et al, 2011 ; Mukherjee et al, 2011 ; Ince-Dunn et al, 2012 ; Scheckel et al, 2016 ).…”