title: 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 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.
authors.affiliation: Committee on Immunology, Department of Pathology, The Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mathew
authors.forename: Michael P
authors.initials: MP
authors.lastname: Seiler
authors.forename: Seth T
authors.initials: ST
authors.lastname: Scanlon
authors.forename: Ai-ping
authors.initials: AP
authors.lastname: Mao
authors.forename: Michael G
authors.initials: MG
authors.lastname: Constantinides
authors.forename: Clara
authors.initials: C
authors.lastname: Bertozzi-Villa
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Singer
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D044842:Cullin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding; D021381:Protein Transport; D051560:Proto-Oncogene Proteins c-bcl-6; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D054875:Ubiquitination; D016335:Zinc Fingers
chemical_list: C490010:Bcl6 protein, mouse; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D051560:Proto-Oncogene Proteins c-bcl-6; C513267:Zbtb16 protein, mouse