Interferon Regulatory Factor 8 (IRF8) Interacts with the B Cell Lymphoma 6 (BCL6) Corepressor BCOR*

Background: Protein partnerships regulate specific functions of cells. BCOR protein-protein interactions are critical to aspects of B cell biology. Results: IRF8 pairs with BCOR in the nucleus to enhance its transcriptional repressive activity. Conclusion: Partnering of IRF8 with BCOR defines a novel mechanism for controlling B cell gene expression. Significance: Understanding gene regulation in specific cell types requires identification of protein complexes that modulate expression. B cell lymphoma 6 (BCL6) corepressor (BCOR) was discovered as a BCL6-interacting corepressor, but little is known about its other biological activities in normal B cell development and function. Previously, we found that interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein, directly targets a large number of genes in germinal center B cells including BCL6. In this study, we screened potential binding partners of IRF8 using a retrovirus-based protein complementation assay screen in a mouse pre-B cell line. We found that IRF8 interacts directly with BCOR and that the α-helical region of IRF8 and the BCL6 binding domain of BCOR are required for this interaction. In addition, IRF8 protein interacts directly with BCL6. Using an siRNA-mediated IRF8 knockdown mouse B cell lymphoma cell line, we showed that IRF8 represses Bcor and enhances Bcl6 transcription. Taken together, these data suggest that a complex comprising BCOR-BCL6-IRF8 modulates BCL6-associated transcriptional regulation of germinal center B cell function.

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