BTB-POZ transcription factors recruit the E3 ubiquitin ligase Cullin 3 to initiate lymphoid effector programs (111.38)

Abstract

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 remodeling. We report that PLZF, the BTB-POZ transcription factor directing the innate-like effector program of NKT thymocytes was prominently associated with cullin 3 (Cul3), an E3 ubiquitin ligase previously shown to use BTB domain-containing proteins as adaptors for substrate binding. PLZF induced the transport of Cul3 from the cytosol to the nucleus where the two proteins were associated within a chromatin associated/modifier protein complex. Furthermore, PLZF expression in thymocytes resulted in selective changes of ubiquitination of multiple components of this complex. Cul3 was also found associated with another BTB-POZ transcription factor, Bcl6, which directs the B cell germinal center program. Conditional deletion in mice demonstrated an absolute, cell-intrinsic requirement of Cul3 for the development of NKT cells and germinal center B cell responses. We conclude that distinct lineage-specific BTB-POZ transcription factors recruit Cul3 to alter the ubiquitination pattern of their associated chromatin associated/modifier complex. We propose that this novel function is essential to direct the differentiation of several T and B lymphocyte effector programs, and may also be involved in the oncogenic role of PLZF and Bcl6 in leukemias and lymphomas.