Regulation of the Development and Function of B Cells by ZBTB Transcription Factors

Abstract

The large ZBTB family comprises a diverse group of transcriptional factors. Several ZBTB proteins have emerged as critical factors that regulate the lineage commitment, differentiation, and function of lymphoid cells as well as many other developmental events. For instance, dysfunctions of ZBTB20 or ZBTB24 have been linked to multisystem failures in humans. Within the B-cell lineage, BCL6, ZBTB7A, ZBTB17, and ZBTB1 regulate the development/differentiation of B cells in both bone marrow and peripheral lymphoid organs, while ZBTB20 and ZBTB32 seem to mainly impact the maintenance of terminal plasma cells. Given the importance of B cells in the prevention and treatment of infectious or autoimmune disorders, we herein summarize the roles of seven ZBTB family members (BCL6, ZBTB7A, ZBTB17, ZBTB20, ZBTB32, ZBTB1, and ZBTB24) in the development, differentiation, and function of B cells as well as the underlying molecular mechanisms.

Keywords: B cells; BCL6; ZBTB1; ZBTB17; ZBTB20; ZBTB24; ZBTB32; ZBTB7A.

Figure 1

Schematic illustrations of the structure and function of ZBTB protein domains. The BTB domain, located at the N-terminus, mediates the protein–protein interactions. The C-terminal zinc fingers (ZFs) mainly mediate the binding to DNA, but they may interact with histone modifiers or other transcriptional factors (TFs) as well. The linker domain is unstructured and often targeted for posttranslational modifications (A). (B) Functional domains of the seven ZBTB proteins discussed in this review. ZBTB24 contains an additional A-T hook domain.

Figure 2

Roles of ZBTB proteins in B-cell development, differentiation, and function. (A) A schematic view of the stages most affected by ZBTB proteins along the B-cell development program. ZBTB7A, ZBTB17, ZBTB1, and BCL6 regulate early B-cell development in the bone marrow, while ZBTB7A, BCL6, ZBTB17, ZBTB1, ZBTB20, ZBTB24, and ZBTB32 function in mature B-cell compartments. Positive/negative regulators are indicated in red/blue, respectively. (B) Regulation of the IL-7R signaling pathway by ZBTB17 in pre-pro-B cells. ZBTB17 plays a dual role by inducing BCL2 while repressing SOCS-1. (C) Transcriptional regulation of genes important for the GC-B or plasma cell (PC) development. Dotted lines represent data obtained in cell lines, and the in vivo functional relevance remains to be confirmed. Tran-B, transitional B cells; LL-PC, long-lived PC.