The RNA-binding Protein HuR is Essential for the B Cell Antibody Response

Overview

Journal Nat Immunol

Date 2015 Feb 24

PMID 25706746

Citations 75

Authors

Manuel D Diaz-Munoz

Sarah E Bell

Kirsten Fairfax

Elisa Monzon-Casanova

Adam F Cunningham

Mar Gonzalez-Porta

Simon R Andrews

Victoria I Bunik

Kathi Zarnack

Tomaz Curk

Ward A Heggermont

Stephane Heymans

Gary E Gibson

Dimitris L Kontoyiannis

Jernej Ule

Martin Turner

Affiliations

Soon will be listed here.

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.

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References

Bunik V, Denton T, Xu H, Thompson C, Cooper A, Gibson G . Phosphonate analogues of alpha-ketoglutarate inhibit the activity of the alpha-ketoglutarate dehydrogenase complex isolated from brain and in cultured cells. Biochemistry. 2005; 44(31):10552-61. DOI: 10.1021/bi0503100. View

Lindhurst M, Fiermonte G, Song S, Struys E, De Leonardis F, Schwartzberg P . Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. Proc Natl Acad Sci U S A. 2006; 103(43):15927-32. PMC: 1595310. DOI: 10.1073/pnas.0607661103. View

Sadri N, Lu J, Badura M, Schneider R . AUF1 is involved in splenic follicular B cell maintenance. BMC Immunol. 2010; 11:1. PMC: 2824733. DOI: 10.1186/1471-2172-11-1. View

Yang L, Shi Q, Ho D, Starkov A, Wille E, Xu H . Mice deficient in dihydrolipoyl succinyl transferase show increased vulnerability to mitochondrial toxins. Neurobiol Dis. 2009; 36(2):320-30. PMC: 3605719. DOI: 10.1016/j.nbd.2009.07.023. View

Pearce E, Poffenberger M, Chang C, Jones R . Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013; 342(6155):1242454. PMC: 4486656. DOI: 10.1126/science.1242454. View

Singh D, Kumar D, Siddiqui Z, Basu S, Kumar V, Rao K . The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal. Cell. 2005; 121(2):281-93. DOI: 10.1016/j.cell.2005.02.036. View

Reth M . Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol. 2002; 3(12):1129-34. DOI: 10.1038/ni1202-1129. View

Vigorito E, Perks K, Abreu-Goodger C, Bunting S, Xiang Z, Kohlhaas S . microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity. 2007; 27(6):847-59. PMC: 4135426. DOI: 10.1016/j.immuni.2007.10.009. View

Richards S, Clark E . BCR-induced superoxide negatively regulates B-cell proliferation and T-cell-independent type 2 Ab responses. Eur J Immunol. 2009; 39(12):3395-403. PMC: 3419136. DOI: 10.1002/eji.200939587. View

10.

Konig J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B . iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol. 2010; 17(7):909-15. PMC: 3000544. DOI: 10.1038/nsmb.1838. View

11.

Zakikhani M, Bazile M, Hashemi S, Javeshghani S, Avizonis D, St Pierre J . Alterations in cellular energy metabolism associated with the antiproliferative effects of the ATM inhibitor KU-55933 and with metformin. PLoS One. 2012; 7(11):e49513. PMC: 3504012. DOI: 10.1371/journal.pone.0049513. View

12.

Kiss G, Konrad C, Doczi J, Starkov A, Kawamata H, Manfredi G . The negative impact of α-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation. FASEB J. 2013; 27(6):2392-406. PMC: 3659355. DOI: 10.1096/fj.12-220202. View

13.

Anders S, Huber W . Differential expression analysis for sequence count data. Genome Biol. 2010; 11(10):R106. PMC: 3218662. DOI: 10.1186/gb-2010-11-10-r106. View

14.

Yang K, Shrestha S, Zeng H, Karmaus P, Neale G, Vogel P . T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity. 2013; 39(6):1043-56. PMC: 3986063. DOI: 10.1016/j.immuni.2013.09.015. View

15.

Doody G, Bell S, Vigorito E, Clayton E, McAdam S, Tooze R . Signal transduction through Vav-2 participates in humoral immune responses and B cell maturation. Nat Immunol. 2001; 2(6):542-7. DOI: 10.1038/88748. View

16.

Mukherjee N, Corcoran D, Nusbaum J, Reid D, Georgiev S, Hafner M . Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol Cell. 2011; 43(3):327-39. PMC: 3220597. DOI: 10.1016/j.molcel.2011.06.007. View

17.

Diaz-Munoz M, Osma-Garcia I, Iniguez M, Fresno M . Cyclooxygenase-2 deficiency in macrophages leads to defective p110γ PI3K signaling and impairs cell adhesion and migration. J Immunol. 2013; 191(1):395-406. DOI: 10.4049/jimmunol.1202002. View

18.

Quinlan C, Goncalves R, Hey-Mogensen M, Yadava N, Bunik V, Brand M . The 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I. J Biol Chem. 2014; 289(12):8312-25. PMC: 3961658. DOI: 10.1074/jbc.M113.545301. View

19.

Le A, Lane A, Hamaker M, Bose S, Gouw A, Barbi J . Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012; 15(1):110-21. PMC: 3345194. DOI: 10.1016/j.cmet.2011.12.009. View

20.

Stuart S, Schauble A, Gupta S, Kennedy A, Keppler B, Bingham P . A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab. 2014; 2(1):4. PMC: 4108059. DOI: 10.1186/2049-3002-2-4. View