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

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 thymocytes, is prominently associated with cullin 3 (CUL3), an E3 ubiquitin ligase previously shown to use BTB domain-containing proteins as adaptors for substrate binding. 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 lymphomas.

Pubmed ID: 23086144

Authors

  • Mathew R
  • Seiler MP
  • Scanlon ST
  • Mao AP
  • Constantinides MG
  • Bertozzi-Villa C
  • Singer JD
  • Bendelac A

Journal

Nature

Publication Data

November 22, 2012

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 5R01GM082940
  • Agency: NIDDK NIH HHS, Id: P30 DK042086
  • Agency: NIAID NIH HHS, Id: R01 AI038339
  • Agency: NIGMS NIH HHS, Id: R01 GM082940
  • Agency: NIAID NIH HHS, Id: R01AI038339
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • B-Lymphocytes
  • Cell Differentiation
  • Cell Line
  • Cullin Proteins
  • DNA-Binding Proteins
  • Kruppel-Like Transcription Factors
  • Mice
  • Protein Binding
  • Protein Transport
  • T-Lymphocytes
  • Ubiquitination
  • Zinc Fingers