Regulation of B-cell survival by BAFF-dependent PKCδ-mediated nuclear signalling

Abstract

Approximately 65% of B cells generated in human bone marrow are potentially harmful autoreactive B cells1. Most of these cells are clonally deleted in the bone marrow, while those autoreactive B cells that escape to the periphery are anergized or perish before becoming mature B cells2,3,4,5. Escape of self-reactive B cells from tolerance permits production of pathogenic auto-antibodies6; recent studies suggest that extended B lymphocyte survival is a cause of autoimmune disease in mice and humans7. Here we report a mechanism for the regulation of peripheral B-cell survival by serine/threonine protein kinase Cδ (PKCδ): spontaneous death of resting B cells is regulated by nuclear localization of PKCδ that contributes to phosphorylation of histone H2B at serine 14 (S14-H2B). We show that treatment of B cells with the potent B-cell survival factor BAFF (‘B-cell-activating factor belonging to the TNF family’) prevents nuclear accumulation of PKCδ. Our data suggest the existence of a previously unknown BAFF-induced and PKCδ-mediated nuclear signalling pathway which regulates B-cell survival.

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Figure 1: PKCδ-deficient B cells are independent of BAFF.
Figure 2: PKCδ promotes B-cell survival.
Figure 3: Nuclear expression of PKCδ in ex vivo isolated B cells is negatively regulated by BAFF.
Figure 4: PKCδ contributes to cell-death-related phosphorylation of S14-H2B.

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Acknowledgements

We thank S. H. Ahn, D. Allis, M. Reyland, U. Siebenlist, the Rockefeller University Genotyping Resource Center and the MSKCC Genomics Core Laboratory for providing cells, vectors, reagents and technical assistance. We also thank E. Besmer for help with manuscript preparation, and A. Patke and members of the Tarakhovsky laboratory for discussions. This work was supported by The Irene Diamond Fund/Professorship Program (A.T.), the NIH (A.T.) and The S.L.E. Foundation (I.M.).

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Correspondence to Alexander Tarakhovsky.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Methods (DOC 37 kb)

Supplementary Figure legends (DOC 28 kb)

Supplementary Figure 1

PKCδ does not control the expression of BAFF and its receptor. (PDF 18 kb)

Supplementary Figure 2

PKCδ does neither control the expression of IL-6 mRNA, secretion of IL-6 nor IL-6-dependent survival of peripheral B cells. (PDF 23 kb)

Supplementary Figure 3

3PKCδ does not control the expression of mRNAs encoding anti- or pro-apoptotic proteins in peripheral B cells and PKCd-deficient cells remain sensitive to BAFF. (PDF 112 kb)

Supplementary Table 1

Mouse microsatellite polymorphic sites used for genotyping of PKCδ-/- mice on C57BL/6 genetic background. (DOC 108 kb)

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Mecklenbräuker, I., Kalled, S., Leitges, M. et al. Regulation of B-cell survival by BAFF-dependent PKCδ-mediated nuclear signalling. Nature 431, 456–461 (2004). https://doi.org/10.1038/nature02955

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