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

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.

References

  1. Savage, A. K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008)

    CAS  Article  Google Scholar 

  2. Kovalovsky, D. et al. The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nature Immunol. 9, 1055–1064 (2008)

    CAS  Article  Google Scholar 

  3. Xu, L. et al. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 425, 316–321 (2003)

    ADS  CAS  Article  Google Scholar 

  4. Furukawa, M., He, Y. J., Borchers, C. & Xiong, Y. Targeting of protein ubiquitination by BTB–Cullin 3–Roc1 ubiquitin ligases. Nature Cell Biol. 5, 1001–1007 (2003)

    CAS  Article  Google Scholar 

  5. Geyer, R., Wee, S., Anderson, S., Yates, J. & Wolf, D. A. BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases. Mol. Cell 12, 783–790 (2003)

    CAS  Article  Google Scholar 

  6. Pintard, L., Willems, A. & Peter, M. Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family. EMBO J. 23, 1681–1687 (2004)

    CAS  Article  Google Scholar 

  7. Zimmerman, E. S., Schulman, B. A. & Zheng, N. Structural assembly of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 20, 714–721 (2010)

    CAS  Article  Google Scholar 

  8. Basso, K. & Dalla-Favera, R. BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv. Immunol. 105, 193–210 (2010)

    CAS  Article  Google Scholar 

  9. McConnell, M. J. & Licht, J. D. The PLZF gene of t(11;17)-associated APL. Curr. Top. Microbiol. Immunol. 313, 31–48 (2007)

    CAS  PubMed  Google Scholar 

  10. Guidez, F. et al. RARα-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 104, 18694–18699 (2007)

    ADS  CAS  Article  Google Scholar 

  11. Yasui, D., Miyano, M., Cai, S., Varga-Weisz, P. & Kohwi-Shigematsu, T. SATB1 targets chromatin remodelling to regulate genes over long distances. Nature 419, 641–645 (2002)

    ADS  CAS  Article  Google Scholar 

  12. Cai, S., Lee, C. C. & Kohwi-Shigematsu, T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nature Genet. 38, 1278–1288 (2006)

    CAS  Article  Google Scholar 

  13. Reddy, K. L., Zullo, J. M., Bertolino, E. & Singh, H. Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 452, 243–247 (2008)

    ADS  CAS  Article  Google Scholar 

  14. Zullo, J. M. et al. DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149, 1474–1487 (2012)

    CAS  Article  Google Scholar 

  15. Ohnuki, H. et al. BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signaling in angiogenesis. Blood 119, 2688–2698 (2012)

    CAS  Article  Google Scholar 

  16. Savage, A. K., Constantinides, M. G. & Bendelac, A. Promyelocytic leukemia zinc finger turns on the effector T cell program without requirement for agonist TCR signaling. J. Immunol. 186, 5801–5806 (2011)

    CAS  Article  Google Scholar 

  17. Kwon, J. E. et al. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. J. Biol. Chem. 281, 12664–12672 (2006)

    CAS  Article  Google Scholar 

  18. Wimuttisuk, W. & Singer, J. D. The Cullin3 ubiquitin ligase functions as a Nedd8-bound heterodimer. Mol. Biol. Cell 18, 899–909 (2007)

    CAS  Article  Google Scholar 

  19. Errington, W. J. et al. Adaptor protein self-assembly drives the control of a Cullin-RING ubiquitin ligase. Structure 20, 1141–1153 (2012)

    CAS  Article  Google Scholar 

  20. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011)

    CAS  Article  Google Scholar 

  21. Hyjek, E., Chadburn, A., Liu, Y. F., Cesarman, E. & Knowles, D. M. BCL-6 protein is expressed in precursor T-cell lymphoblastic lymphoma and in prenatal and postnatal thymus. Blood 97, 270–276 (2001)

    CAS  Article  Google Scholar 

  22. Braun, S. et al. The Cul4-Ddb1Cdt2 ubiquitin ligase inhibits invasion of a boundary-associated antisilencing factor into heterochromatin. Cell 144, 41–54 (2011)

    CAS  Article  Google Scholar 

  23. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004)

    ADS  CAS  Article  Google Scholar 

  24. Bosch-Presegué, L. et al. Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol. Cell 42, 210–223 (2011)

    Article  Google Scholar 

  25. Du, Z. et al. DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Sci. Signal. 3, ra80 (2010)

    Article  Google Scholar 

  26. Hernández-Muñoz, I. et al. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc. Natl Acad. Sci. USA 102, 7635–7640 (2005)

    ADS  Article  Google Scholar 

  27. Hargreaves, D. C. & Crabtree, G. R. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 21, 396–420 (2011)

    CAS  Article  Google Scholar 

  28. Sowa, M. E., Bennett, E. J., Gygi, S. P. & Harper, J. W. Defining the human deubiquitinating enzyme interaction landscape. Cell 138, 389–403 (2009)

    CAS  Article  Google Scholar 

  29. Beisel, C. & Paro, R. Silencing chromatin: comparing modes and mechanisms. Nature Rev. Genet. 12, 123–135 (2011)

    CAS  Article  Google Scholar 

  30. McEvoy, J. D., Kossatz, U., Malek, N. & Singer, J. D. Constitutive turnover of cyclin E by Cul3 maintains quiescence. Mol. Cell. Biol. 27, 3651–3666 (2007)

    CAS  Article  Google Scholar 

  31. Jin, J., Ang, X. L., Shirogane, T. & Wade Harper, J. Identification of substrates for F-box proteins. Methods Enzymol. 399, 287–309 (2005)

    CAS  Article  Google Scholar 

  32. Rush, J. et al. Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature Biotechnol. 23, 94–101 (2005)

    CAS  Article  Google Scholar 

  33. Benlagha, K., Wei, D. G., Veiga, J., Teyton, L. & Bendelac, A. Characterization of the early stages in thymic NKT cell development. J. Exp. Med. 202, 485–492 (2005)

    CAS  Article  Google Scholar 

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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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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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The authors declare no competing financial interests.

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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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