The RNA-binding protein HuR is essential for the B cell antibody response

doi:10.1038/ni.3115

. 2015 Apr;16(4):415-25.

doi: 10.1038/ni.3115. Epub 2015 Feb 23.

The RNA-binding protein HuR is essential for the B cell antibody response

Manuel D Diaz-Muñoz¹, Sarah E Bell¹, Kirsten Fairfax², Elisa Monzon-Casanova¹, Adam F Cunningham³, Mar Gonzalez-Porta⁴, Simon R Andrews⁵, Victoria I Bunik⁶, Kathi Zarnack⁷, Tomaž Curk⁸, Ward A Heggermont⁹, Stephane Heymans¹⁰, Gary E Gibson¹¹, Dimitris L Kontoyiannis¹², Jernej Ule¹³, Martin Turner¹

Affiliations

¹ Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK.
² 1] Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK. [2] The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
³ MRC Centre for Immune Regulation, Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham, UK.
⁴ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK.
⁵ Bioinformatics Group, The Babraham Institute, Cambridge, UK.
⁶ A. N. Belozersky Institute of PhysicoChemical Biology and Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
⁷ Buchmann Institute for Molecular Life Sciences, Frankfurt, Germany.
⁸ University of Ljubljana, Faculty of Computer and Information Science, Ljubljana, Slovenia.
⁹ Center for Molecular and Vascular Biology, KU Leuven, Belgium.
¹⁰ 1] Center for Molecular and Vascular Biology, KU Leuven, Belgium. [2] Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
¹¹ Weill Cornell Medical College, Brain and Mind Research Institute, Burke Medical Research Institute, White Plains, New York, USA.
¹² Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
¹³ UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK.

PMID: 25706746
PMCID: PMC4479220
DOI: 10.1038/ni.3115

The RNA-binding protein HuR is essential for the B cell antibody response

Manuel D Diaz-Muñoz et al. Nat Immunol. 2015 Apr.

. 2015 Apr;16(4):415-25.

doi: 10.1038/ni.3115. Epub 2015 Feb 23.

Authors

Affiliations

¹ Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK.
² 1] Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK. [2] The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
³ MRC Centre for Immune Regulation, Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham, UK.
⁴ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK.
⁵ Bioinformatics Group, The Babraham Institute, Cambridge, UK.
⁶ A. N. Belozersky Institute of PhysicoChemical Biology and Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
⁷ Buchmann Institute for Molecular Life Sciences, Frankfurt, Germany.
⁸ University of Ljubljana, Faculty of Computer and Information Science, Ljubljana, Slovenia.
⁹ Center for Molecular and Vascular Biology, KU Leuven, Belgium.
¹⁰ 1] Center for Molecular and Vascular Biology, KU Leuven, Belgium. [2] Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
¹¹ Weill Cornell Medical College, Brain and Mind Research Institute, Burke Medical Research Institute, White Plains, New York, USA.
¹² Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
¹³ UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK.

PMID: 25706746
PMCID: PMC4479220
DOI: 10.1038/ni.3115

Abstract

Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells.

PubMed Disclaimer

Figures

**Figure 1. HuR expression is increased during B cell activation**
**(a)** qPCR analysis of *Elavl1* (HuR), *Elavl2, Elavl3* and *Elavl4* mRNA expression in *ex vivo* splenic B cells (n=6) and brain (n=2). Data shown relative to *Elavl1* mRNA expression (ND = not detected). **(b)** Intracellular HuR staining in B cell subsets in the bone marrow (BM). **(c)** HuR protein expression in splenic B cell subsets. B cell populations in BM and spleen in *Mb1-*Cre (unfloxed controls, Ctrl.) and *Elavl1*^fl/flMb1-Cre (HuR-cKO) mice were analysed by flow cytometry as described in online methods. **(d)** Quantification of HuR expression. Median Fluorescence Intensity (MFI) of HuR staining relative to an isotype control (IC) antibody is shown (n=3 biological replicates). Dashed line indicates the detection limit of the assay. **(e)** Normalised HuR mRNA expression in GC B cells (B220⁺CD95⁺PNA⁺) relative to the expression of HuR mRNA in non-GC B cells (B220⁺PNA⁻CD95⁻). A representative dot plot is shown to indicate cell sorting strategy. Cells from individual mice were isolated independently for mRNA expression analysis. Data from each individual sample and the mean value are shown (n=3-4 per group, unpaired t-test). **(f)** HuR protein expression in non-GC and GC B cells from individual immunised mice measured by flow cytometry. Data from each individual sample and the mean value are shown. (n=6, unpaired t-test). Histograms and dot plots shown in b, c, e and f are representative of more than 3 independent stainings using individual mice. **(g)** Time course analysis of HuR expression after *in vitro* B cell activation with LPS or αCD40+IL-4+IL-5. Immunoblots are representative of four (activation with LPS) or two (activation with αCD40+IL-4+IL-5) independent experiments respectively. In each experiment, HuR (Abs₇₉₄) expression was normalised by β-actin levels and quantified relative to non-activated B cells. Data is shown as mean value.

**Figure 2. HuR-cKO mice have no major defects in B cell development**
**(a)** Analysis of B cell populations in the bone marrow of *Mb1-*Cre (Ctrl) and *Elavl1*^fl/flMb1-Cre (HuR-cKO) mice. Representative dot plots summarise the cell gating strategy and cell frequency. The number of Pre-, immature-, and mature-B cells was calculated based on the expression of surface cell markers. **(b)** Quantitation of the number of different B cell subsets in the spleen of Ctrl. and HuR-cKO mice. T1, T2, T3, FO and MZ B cells were defined based on cell surface markers as described in the online methods. **(c)** Analysis of the number of CD19⁺ cells in peripheral lymph nodes. **(d)** Analysis of B1 B cells in the peritoneal cavity. Representative dot plots summarise the cell gating strategy and cell frequency. Analysed data shown in a, b, c and d are from individual mice of each genotype and is representative of more than 3 independent experiments (n=8 per group; Mann-Whitney analysis was performed; *p<0.05, **p<0.005, ***p<0.0005). **(e)** Representative flow cytometry plots of BrdU incorporation in Pre-B cells after 2.5 hours labelling. The mean percentage ± SD of BrdU⁺ cells is shown (n=8 per group). **(f)** Analysis of BrdU⁺ mature B cells following 7 days labelling. Representative dot plots and contour plots are shown. The mean percentage ± SD of BrdU⁺ cells is shown (n=5 individual mice per group).

**Figure 3. B cells require HuR for responses to different classes of antigens**
**(a)** Quantitation of serum immunoglobulin in non-immunised mice. Samples from individual Mb1-Cre (Ctrl) and *Elavl1*^fl/flMb1-Cre (HuR-cKO) mice were collected in two independent experiments (n=10; Mann-Whitney test). **(b, c)** Analysis of NP-reactive IgM and IgG₃ antibodies present in serum samples from individual mice of each genotype collected 7 days after immunization with NP-LPS (b) or NP-Ficoll (c). Dot line indicates the limit of detection in this assay (n=6 per group in b; n=6-7 per group in c; Mann-Whitney test). **(d)** Time course analysis of NP23 reactive IgM and IgG₁ in serum of mice immunised with NP-KLH at day 0 and day 42. **(e)** Ratio of NP2- bound (high affinity) and NP23-bound (low + high affinity) IgG₁ antibodies. Data is shown in d and e as mean ± SEM, n=6/group. Statistical analysis of the data at each time point was performed using a Mann-Whitney test (p<0.005 in all cases). **(f)** The number of GC B cells present in the spleen of *Mb1-*Cre (Ctrl) and HuR-cKO mice seven days after immunization with NP-KLH. Representative dot plots show the gating strategy and frequency of GC B cells (B220⁺ PNA⁺ CD95⁺ cells). The number of GC cells in individual mice of each genotype (n= 7-8 mice) from one of the two independent experiments performed is shown (Mann-Whitney test). **(g)** ELISPOT of the number of IgM and IgG₁ ASC present in the spleens of the mice analysed in f (n=7-8, Mann-Whitney test). **(h, i)** Quantitation of IgM-ASC and IgG₁-ASC present in spleen (h) and BM (i) of *Mb1-*Cre (Ctrl.) and HuR-cKOmice seven days after secondary immunization. Data from each individual mice of each group is shown (n=7-8; Mann-Whitney test) (*p<0.05, **p<0.005, ***p<0.0005).

**Figure 4. Genes involved in energy metabolism are deregulated in HuR-deficient B cells**
**(a)** Analysis of the fold change in mRNA expression and mRNA translation (HuR-cKO/Ctrl) of those genes involved in cell energy pathways (Glycolysis and Gluconeogenesis, TCA Cycle and Electron Transport Chain) that are differentially translated in the absence of HuR (number of genes=25). mRNAseq and Ribo-seq libraries were generated in two independent experiments using LPS-activated splenic B cells from *Elavl1*^fl/flMb1^+/+ (Ctrl) and *Elavl1*^fl/flMb1-Cre (HuR-cKO) mice (RNAseq, n=3-4 per group; Ribo-seq, n=5 per group). **(b)** Statistical significance of changes in mRNA expression and translation of the genes shown in a. P adjusted values (padj) were calculated after multiple correction of p values (Benjamini-Hochberg correction) obtained from DESeq analysis of RNAseq and Ribo-seq datasets. **(c)** *Dlst* mRNA splicing profiles in Ctrl and HuR-cKO B cells. Representative sashimi plots were generated in IGV. The exon number and read counts across each exon-exon junction are indicated for representative mRNAseq data from *ex vivo* and mitogen activated B cells. HuR iCLIP data for the *Dlst* locus collected from three independent experiments is shown as unique single nucleotide crosslink sites.

**Figure 5. HuR regulates intron usage in B cells**
**(a)** Proportion of unique HuR crosslink sites annotated to each genomic features. The sum of unique cDNA counts from three independent iCLIP experiments performed with LPS-activated B cells (Supplementary Fig. 5) was used for peak call analysis (FDR<0.05) and quantification of HuR crosslink sites. **(b)** RNA map of crosslink sites assessed at the exon-intron boundaries (BP=branch point; 5′ SS=5′ splice site; 3′ SS=3′ splice site). **(c)** Correlation between HuR binding and differential intron expression in HuR-cKO B cells. **(d)** Venn-diagram showing the relationship between genes with differential intron expression (Genes), differential mRNA expression (mRNAs) and mRNA bound by HuR (Targets). **(e)** Relationship between genes with differential intron expression (Genes), differential ribosome occupancy (mRNAs) and HuR binding (Targets). **(f)** Identification of mRNAs with differential intron expression which are both differentially expressed and differentially translated. **(g)** Global analysis of the fold change (HuR-cKO/Ctrl) (log2) in mRNA expression of all genes; genes with differential intron expression (group 1; n=375); HuR-targeted genes with differential intron usage and differential RNA abundance (group 2; n=64); HuR-targeted genes with differential intron usage and differential ribosome occupancy (group 3; n=71); and HuR-targeted genes with differential intron expression which are both differentially expressed and differentially translated (group 4; n=25). **(h)** Global analysis of the fold change (HuR-cKO/Ctrl) (log2) in ribosome occupancy in the groups described in g. Data in g and h is shown as box whisker plots showing the mean ± SD and 10-90 percentiles. Wilcoxon signed-rank test was performed between each group against all genes (* p<0.05, ** p<0.005). **(i)** Heatmap of the fold change (HuR-cKO/Ctrl) (log2) in mRNA expression of genes in group 4. **(j)** Heatmap showing the fold change (HuR-cKO/Ctrl) (log2) in ribosome occupancy of genes in group 4. Genes previously annotated as alternative spliced are highlighted in blue.

**Figure 6. Alternative splicing of *Dlst* in HuR-cKO B cells reduces αKGDH enzymatic activity**
**(a)** Design summary of PCR primers, spanning exon 10/intron 10 junction and intron 10/exon 11 junction, used to detect intron inclusion in *Elavl1*^fl/flMb1-Cre (HuR-cKO) B cells. Intron inclusion in *ex vivo* and LPS-activated B cells was quantified relative to *Elavl1*^fl/flMb1^+/+ (Ctrl) cells. **(b)** PCR across the exon 10/exon 11 junction. The percentage of alternative exon inclusion was calculated after gel density quantification of long (alternative exon included) and short (alternative exon skipped) amplicons. Data in a and b was from 6 (naïve cells) or 4 (LPS-treated cells) biological replicates collected in two independent experiments and is shown as mean values ± SD (unpaired t test; * p<0.05, *** p<0.0005). Images are representative. **(c)** *Dlst* reads measured by mRNAseq in *ex vivo* and LPS-activated B cells from Ctrl and HuR-cKO mice. Mean normalised read counts ± SD are shown (n=3-4 per group; differential expression analysis performed with DESeq; *padj<0.05, ***padj < 0.0005). **(d)** Quantification of ribosome footprints mapped to *Dlst* mRNA. Data from *ex vivo* and LPS-activated B cells is shown as mean normalised read counts ± SD (n=4-5 per group; differential expression analysis performed using DESeq2; ***padj < 0.0005). **(e)** Immunoblot analysis of Dlst protein. Total protein lysates were prepared from *ex vivo* and LPS-activated splenic B cells from *Elval1*^fl/flMb1^+/+ (Ctrl) and HuR-cKO mice in three independent experiments and loaded in the same gel. β-actin was detected as sample loading control. **(f)** Gel density quantification of Dlst protein abundance relative to β-actin (n=3 per group; unpaired t test; *p<0.05). **(g)** αKGDH enzymatic activity in total cell extracts from *ex vivo* B cells collected from individual *Elavl1*^fl/flMb1^+/+ (Ctrl.) and HuR-cKO mice (Mean ± SD; n=4 per group from two independent experiments; unpaired t test; *p<0.05).

**Figure 7. αKGDH enzymatic activity is required for B cell survival and proliferation**
**(a)** Viability of splenic B cells activated with LPS + IL-4 (96 h) in the presence of the indicated doses of succinyl phosphonate (SP) or phosphonoethyl ester of succinyl phosphonate (PESP). Data from one of the two independent experiments performed is shown as mean ± SD (n=4 per group; unpaired t tests comparing control samples against each different dose; *p<0.05, **p<0.01, ***p<0.001). **(b)** Representative CellTrace^™ Violet (CTV) dye profiles in the presence of SP and PESP. The number of cells in each generation was calculated based on dye dilution. **(c)** *In vitro* proliferation of *Dlst*^+/+ and *Dlst*^+/− splenic B cells after activation with LPS + IL-4 for 96 hours analysed by CellTrace^™ Violet dye dilution as described in b. Splenic B cells were isolated from 6 different mice and treated separately in two independent experiments. Data are shown as the mean number of cells per generation ± SD. Two way ANOVA test was performed (p=0.0162). **(d)** Quantification of the number of IgG₁⁺ cells in cultures described in c. Representative plots show CellTrace^™ Violet dye dilution versus IgG₁ surface expression. Unpaired Student’s t test was performed for statistical analysis of the data (n=6; *p<0.05). **(e)** Analysis of CSR in the cultures in a. Representative plots and the mean number of IgG₁⁺ cells ± SD from one of the two independent experiments are shown (n=4 per group; unpaired Student’s t test comparing no treated cells against the other conditions; *p<0.05, **p<0.01, ***p<0.001).

**Figure 8. ROS scavengers rescue HuR-deficient B cells from cell death**
**(a)** Representative plots showing H₂DCFDA and DAPI staining of *Mb1-*Cre (Ctrl) and HuR-cKO B cells after four hours of *in vitro* culture in the absence or presence of recombinant catalase (Cat, 20 U/ml). **(b)** Quantitation of the number of DAPI⁺ cells and the MFI of H₂DCFDA in DAPI⁻ cells in the cultures described in a (Mean ± SD, n=3 per group). **(c)** Effect of Q-VD-OPh (3 μM) and Necrostatin-1 (Nec-1, 3 μM) on *in vitro* B cell survival (Mean number of DAPI⁻ cells ± SD, n=4 per group). **(d)** Representative CellTrace^™ Violet dye profiles of LPS + IL-4 stimulated *Mb1-*Cre (Ctrl.) and HuR-cKO B cells cultured in complete RPMI media supplemented with catalase (20 U/ml), L-N-acetyl-cysteine (L-NAC, 10 mM) or EUK-134 (5 μM) for 96 hours. (e) Number of live cells in each cell generation of the proliferation profile shown in d (Mean ± SD, n=3 per group). **(f)** Representative plots and the mean number of IgG₁⁺ cells ± SD. **(g)** Representative plots and the mean number of CD138⁺ cells ± SD is shown. Data shown in each figure panel is from one of the at least three independent experiments performed. Unpaired Student’s t tests were performed for statistical analysis of the data (*p<0.05,**p<0.01,***p<0.001).

See this image and copyright information in PMC

Cited by

RNA-Binding Protein HuR Promotes Th17 Cell Differentiation and Can Be Targeted to Reduce Autoimmune Neuroinflammation.
Chen J, Martindale JL, Abdelmohsen K, Kumar G, Fortina PM, Gorospe M, Rostami A, Yu S. Chen J, et al. J Immunol. 2020 Apr 15;204(8):2076-2087. doi: 10.4049/jimmunol.1900769. Epub 2020 Mar 13. J Immunol. 2020. PMID: 32169842 Free PMC article.
Redox regulation of immunometabolism.
Muri J, Kopf M. Muri J, et al. Nat Rev Immunol. 2021 Jun;21(6):363-381. doi: 10.1038/s41577-020-00478-8. Epub 2020 Dec 18. Nat Rev Immunol. 2021. PMID: 33340021 Review.
Understanding and targeting the disease-related RNA binding protein human antigen R (HuR).
Schultz CW, Preet R, Dhir T, Dixon DA, Brody JR. Schultz CW, et al. Wiley Interdiscip Rev RNA. 2020 May;11(3):e1581. doi: 10.1002/wrna.1581. Epub 2020 Jan 23. Wiley Interdiscip Rev RNA. 2020. PMID: 31970930 Free PMC article. Review.
Genome-wide assessment of differential translations with ribosome profiling data.
Xiao Z, Zou Q, Liu Y, Yang X. Xiao Z, et al. Nat Commun. 2016 Apr 4;7:11194. doi: 10.1038/ncomms11194. Nat Commun. 2016. PMID: 27041671 Free PMC article.
HuR controls apoptosis and activation response without effects on cytokine 3' UTRs.
Karginov FV. Karginov FV. RNA Biol. 2019 May;16(5):686-695. doi: 10.1080/15476286.2019.1582954. Epub 2019 Mar 4. RNA Biol. 2019. PMID: 30777501 Free PMC article.

See all "Cited by" articles

References

1. Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342:1242454. - PMC - PubMed
1. Caro-Maldonado A, et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol. 2014;192:3626–3636. - PMC - PubMed
1. Blair D, Dufort FJ, Chiles TC. Protein kinase Cbeta is critical for the metabolic switch to glycolysis following B-cell antigen receptor engagement. The Biochemical journal. 2012;448:165–169. - PubMed
1. Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD. The genetic network controlling plasma cell differentiation. Seminars in immunology. 2011;23:341–349. - PubMed
1. Calado DP, et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nature immunology. 2012;13:1092–1100. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in GEO
Actions
- Search in PubMed
- Search in GEO
Actions
- Search in PubMed
- Search in GEO

Grants and funding

BB/J00152X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom

LinkOut - more resources

Full Text Sources
Other Literature Sources
- H1 Connect
- scite Smart Citations
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Miscellaneous
- NCI CPTAC Assay Portal

[1] Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342:1242454. - PMC - PubMed

[2] Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342:1242454. - PMC - PubMed

[3] Caro-Maldonado A, et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol. 2014;192:3626–3636. - PMC - PubMed

[4] Caro-Maldonado A, et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol. 2014;192:3626–3636. - PMC - PubMed

[5] Blair D, Dufort FJ, Chiles TC. Protein kinase Cbeta is critical for the metabolic switch to glycolysis following B-cell antigen receptor engagement. The Biochemical journal. 2012;448:165–169. - PubMed

[6] Blair D, Dufort FJ, Chiles TC. Protein kinase Cbeta is critical for the metabolic switch to glycolysis following B-cell antigen receptor engagement. The Biochemical journal. 2012;448:165–169. - PubMed

[7] Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD. The genetic network controlling plasma cell differentiation. Seminars in immunology. 2011;23:341–349. - PubMed

[8] Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD. The genetic network controlling plasma cell differentiation. Seminars in immunology. 2011;23:341–349. - PubMed

[9] Calado DP, et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nature immunology. 2012;13:1092–1100. - PMC - PubMed

[10] Calado DP, et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nature immunology. 2012;13:1092–1100. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The RNA-binding protein HuR is essential for the B cell antibody response

Affiliations

The RNA-binding protein HuR is essential for the B cell antibody response

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Associated data

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous