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

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...

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Published inNature immunology Vol. 16; no. 4; pp. 415 - 425
Main Authors Diaz-Muñoz, Manuel D, Bell, Sarah E, Fairfax, Kirsten, Monzon-Casanova, Elisa, Cunningham, Adam F, Gonzalez-Porta, Mar, Andrews, Simon R, Bunik, Victoria I, Zarnack, Kathi, Curk, Tomaž, Heggermont, Ward A, Heymans, Stephane, Gibson, Gary E, Kontoyiannis, Dimitris L, Ule, Jernej, Turner, Martin
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.04.2015
Subjects
Acyltransferases - genetics
Acyltransferases - immunology
Alternative Splicing - immunology
Animals
Antigens - administration & dosage
Antigens - immunology
B-Lymphocytes - cytology
B-Lymphocytes - drug effects
B-Lymphocytes - immunology
Cell Death
Cell Differentiation
Cell Proliferation
ELAV Proteins - genetics
ELAV Proteins - immunology
Erythrocytes - immunology
Germinal Center - cytology
Germinal Center - drug effects
Germinal Center - immunology
Immunity, Humoral
Immunization
Immunoglobulin Class Switching
Immunoglobulins - biosynthesis
Lipopolysaccharides - pharmacology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria - genetics
Mitochondria - immunology
Reactive Oxygen Species - immunology
Reactive Oxygen Species - metabolism
RNA, Messenger - genetics
RNA, Messenger - immunology
Sheep
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Summary: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.
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Current address: The Department of Experimental Medicine, University of Melbourne, Parkville, Victoria 3052, Australia.
AUTHOR CONTRIBUTIONS
M.D.D.M., S.E.B., K.F. and M.T. designed and performed experiments. M.D.D.M. and M.T. designed and performed all high-throughput sequencing experiments. M.D.D.M., E.M.C., M.G.P., S.A. and K.Z. participated in bioinformatics analysis. T.C. and J.U. designed iCount pipeline for iCLIP analysis. V.I.B. provided the SP and PESP inhibitors and advised on their cellular application and action. D.L.K. provided the Elavl1tm1Dkon mice. S.H. and G.E.G. provided the Dlst+/− mice generated by Lexicon Pharmaceuticals, Inc. W.A.H. helped with procedures in Dlst+/− mice. M.D.D.M. and M.T. wrote the manuscript.
ISSN:1529-2908
1529-2916
DOI:10.1038/ni.3115