BRAD4 plays a critical role in germinal center response by regulating Bcl-6 and NF-κB activation

Fangjie Gao; Yuanyuan Yang; Zhengyi Wang; Xiaoming Gao; Biao Zheng

doi:10.1016/j.cellimm.2015.01.010

BRAD4 plays a critical role in germinal center response by regulating Bcl-6 and NF-κB activation

Cell Immunol. 2015 Mar;294(1):1-8. doi: 10.1016/j.cellimm.2015.01.010. Epub 2015 Jan 28.

Authors

Fangjie Gao¹, Yuanyuan Yang¹, Zhengyi Wang², Xiaoming Gao³, Biao Zheng⁴

Affiliations

¹ Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
² Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China. Electronic address: zywang01@sibs.ac.cn.
³ Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China. Electronic address: xmgao@suda.edu.cn.
⁴ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bzheng@bcm.edu.

PMID: 25656449
DOI: 10.1016/j.cellimm.2015.01.010

Abstract

Germinal center (GC) reaction is a T cell-dependent process in which activated B cells undergo clonal expansion and functional maturation to produce high affinity antibodies and differentiate into memory B cells(1). Here we demonstrate a new role of bromodomain and extraterminal domain (BET) protein BRD4 in GC B cell development. We found that during B cell differentiation stage there was an elevated expression of BRD4 in GC B cells and inhibition of BRD4 by small molecule inhibitors led to the suppression of GC formation and correspondent antibody responses in a Td antigen immunization model. At the molecular level, we found that the effects of BRD4 in primary GC B cell differentiation and B cell lymphoma were mediated through the impaired phosphorylation and translocation of NF-κBp65 and further down-regulation of B-cell lymphoma 6 (Bcl6) expression. Thus this study reveals a novel function of BRD4 in controlling the GC B cell development pathway.

Keywords: Antibody responses; BRD4; Bcl6; Germinal center B cells.

Published by Elsevier Inc.

MeSH terms

Animals
Antibodies / blood
Antibodies / immunology
Azepines / pharmacology
B-Lymphocytes / cytology*
B-Lymphocytes / immunology
Basic-Leucine Zipper Transcription Factors / biosynthesis
CD4-Positive T-Lymphocytes / immunology
Cell Cycle Proteins
Cell Differentiation / immunology
Gene Expression Regulation / immunology
Germinal Center / immunology*
Humans
Interferon Regulatory Factors / biosynthesis
Lymphocyte Activation / immunology
Lymphoma, B-Cell / pathology
Mice
Mice, Inbred C57BL
Nuclear Proteins / genetics
Nuclear Proteins / physiology*
Nucleoproteins / immunology
PAX5 Transcription Factor / biosynthesis
Phosphorylation
Proto-Oncogene Proteins c-bcl-6 / biosynthesis
Proto-Oncogene Proteins c-bcl-6 / genetics
Proto-Oncogene Proteins c-bcl-6 / immunology*
RNA Interference
RNA, Messenger / biosynthesis
RNA, Small Interfering
Signal Transduction / immunology
Transcription Factor RelA / immunology*
Transcription Factor RelA / metabolism
Transcription Factors / genetics
Transcription Factors / physiology*
Triazoles / pharmacology

Substances

(+)-JQ1 compound
Antibodies
Azepines
BRD4 protein, human
Bach2 protein, mouse
Basic-Leucine Zipper Transcription Factors
Brd4 protein, mouse
Cell Cycle Proteins
Interferon Regulatory Factors
Nuclear Proteins
Nucleoproteins
PAX5 Transcription Factor
Pax5 protein, mouse
Proto-Oncogene Proteins c-bcl-6
RNA, Messenger
RNA, Small Interfering
Rela protein, mouse
Transcription Factor RelA
Transcription Factors
Triazoles
interferon regulatory factor-8