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BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs

Nature volume 491, pages 618–621 (2012)Cite this article

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Abstract

The differentiation of several T- and B-cell effector programs in the immune system is directed by signature transcription factors that induce rapid epigenetic remodelling. Here we report that promyelocytic leukaemia zinc finger (PLZF), the BTB-zinc finger (BTB-ZF) transcription factor directing the innate-like effector program of natural killer T-cell thymocytes1,2, is prominently associated with cullin 3 (CUL3), an E3 ubiquitin ligase previously shown to use BTB domain-containing proteins as adaptors for substrate binding3,4,5,6,7. PLZF transports CUL3 to the nucleus, where the two proteins are associated within a chromatin-modifying complex. Furthermore, PLZF expression results in selective ubiquitination changes of several components of this complex. CUL3 was also found associated with the BTB-ZF transcription factor BCL6, which directs the germinal-centre B cell and follicular T-helper cell programs. Conditional CUL3 deletion in mice demonstrated an essential role for CUL3 in the development of PLZF- and BCL6-dependent lineages. We conclude that distinct lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the ubiquitination pattern of their associated chromatin-modifying complex. We propose that this new function is essential to direct the differentiation of several T- and B-cell effector programs, and may also be involved in the oncogenic role of PLZF and BCL6 in leukaemias and lymphomas8,9.

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Figure 1: Interaction and colocalisation of CUL3 with PLZF.
Figure 2: Ubiquitination changes after PLZF expression.
Figure 3: Lymphocyte development and function in Cul3 cd4 Δ/ Δ mice.
Figure 4: Lymphocyte development and function in Cul3 cd19 Δ/ Δ mice.

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Acknowledgements

We thank A. Dinner, J. Licht, G. Prive, A. Ruthenburg, R. Sciammas, H. Singh and P. Wilson for discussions, J. C. Silva and M. Stokes for UbiScan analysis, C. Labno and V. Bindokas for help with confocal microscopy, and K. Block, L. Roach, D. Zabner, F. Meng and L. Bai for help with experiments. This work was supported by National Institute of Health (NIH) grants 5RO1GM082940 (J.D.S.) and RO1AI038339 (A.B.), and an Irvington Institute postdoctoral fellowship from the Cancer Research Institute (R.M.). A.B. is a Howard Hughes Medical Institute Investigator.

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  1. Department of Pathology, Committee on Immunology, The Howard Hughes Medical Institute, University of Chicago, Chicago, 60637, Illinois, USA

    Rebecca Mathew, Michael P. Seiler, Seth T. Scanlon, Ai-ping Mao, Michael G. Constantinides, Clara Bertozzi-Villa & Albert Bendelac

  2. Department of Biology, Portland State University, Portland, 96207, Oregon, USA

    Jeffrey D. Singer

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Contributions

R.M. designed the research, performed experiments and analysed data. M.P.S., S.T.S., A.M., M.G.C. and C.B.-V. performed experiments and analysed data. J.D.S. helped to design experiments and provided the Cul3fl/fl mice and CUL3 constructs. R.M. and A.B. co-wrote the paper. A.B. supervised the research.

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Correspondence to Albert Bendelac.

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Mathew, R., Seiler, M., Scanlon, S. et al. BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs. Nature 491, 618–621 (2012). https://doi.org/10.1038/nature11548

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