Journal Article

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

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

2012

Overview

The E3 ubiquitin ligase cullin 3 is shown to bind BTB-zinc finger transcription factors to direct the ubiquitination of nuclear chromatin-associated factors to control transcription and cell-fate decisions in B- and T-cell populations. Cullin 3 regulation of immune-cell fate The E3 ubiquitin ligase cullin 3 is shown to direct the ubiquitination of nuclear chromatin-associated factors to control transcription and cell-fate decisions in B- and T-cell populations. The authors suggest that, in addition to directing the differentiation of T- and B-cell effector programs, this previously unrecognized function of cullin 3 may also be involved in the oncogenic role of the proteins PLZF and BCL6 in leukaemias and lymphomas. 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 1 , 2 , is prominently associated with cullin 3 (CUL3), an E3 ubiquitin ligase previously shown to use BTB domain-containing proteins as adaptors for substrate binding 3 , 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 lymphomas 8 , 9 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/45/474/2073 / 631/45/612/822 / 631/80/474/582 / Animals / B-Lymphocytes - cytology / B-Lymphocytes - metabolism / Biological and medical sciences / Cell Differentiation / Cell Line / Cullin Proteins - chemistry / Cullin Proteins - genetics / Cullin Proteins - metabolism / DNA-Binding Proteins - metabolism / Experiments / Fundamental and applied biological sciences. Psychology / Fundamental immunology / Humanities and Social Sciences / Immune system / Immunobiology / Kruppel-Like Transcription Factors - metabolism / letter / Leukemia / Lymphocyte transformation / Lymphocytes / Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation / Mass spectrometry / Mice / Microscopy / multidisciplinary / Promyelocytic Leukemia Zinc Finger Protein / Protein Binding / Protein Transport / Proteins / Proto-Oncogene Proteins c-bcl-6 / Science / T-Lymphocytes - cytology / T-Lymphocytes - metabolism / Ubiquitin-proteasome system / Ubiquitination / Zinc finger proteins / Zinc Fingers