POK/ZBTB proteins: an emerging family of proteins that regulate lymphoid development and function

Abstract

The germinal center (GC) is a unique histological structure found in peripheral lymphoid organs. GCs provide an important source of humoral immunity by generating high affinity antibodies against a pathogen. The GC response is tightly regulated during clonal expansion, immunoglobulin modification, and affinity maturation, whereas its deregulation has a detrimental effect on immune function, leading to development of diseases, such as lymphoma and autoimmunity. LRF (lymphoma/leukemia-related factor), encoded by the ZBTB7A gene, is a transcriptional repressor belonging to the POK (POZ and Krüppel)/ZBTB (zing finger and BTB) protein family. LRF was originally identified as a PLZF (promyelocytic leukemia zinc finger) homolog that physically interacts with BCL6 (B-cell lymphoma 6), whose expression is required for GC formation and associated with non-Hodgkin's lymphoma. Recently, our group demonstrated that LRF plays critical roles in regulating lymphoid lineage commitment, mature B-cell development, and the GC response via distinct mechanisms. Herein, we review POK/ZBTB protein function in lymphoid development, with particular emphasis on the role of LRF in GC B cells.

Fig. 1. Structure of POK family members

The evolutionarily conserved POZ domain (yellow triangles) functions in homo- and heterodimerization and recruits corepressor complexes. Zinc fingers (green squares) mediate specific DNA sequence recognition and binding within gene-regulatory regions. The function of these family members as transcription factors is described in the indicated references.

Fig. 2. LRF protein is highly expressed in GC B-cells, as is Bcl6

Immunohistochemical analysis for LRF in the spleen of an immunized WT mouse (left) and Bcl6 staining in an adjacent section (right) (picture adopted from Sakurai et al (35)). Bcl6 is exclusively expressed in GC B-cells [strong brown staining in the right panel (arrowheads)], while LRF is highly expressed in GC-B cells as well as in other cell types (e.g. erythroid cells).

Fig. 3. Regulation of LRF through two distinct mechanisms

LRF regulates mature B cell (FOB versus MZB) lineage fate determination presumably by counteracting the Notch2/Dll1 pathway. LRF also regulates GC B-cell proliferation and survival by repressing ARF.