The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim

被引:35
|
作者
Jurado, Sabine [1 ,2 ]
Gleeson, Kimberly [1 ]
O'Donnell, Kristy [3 ]
Izon, David J. [1 ,2 ]
Walkley, Carl R. [1 ,2 ]
Strasser, Andreas [3 ,4 ]
Tarlinton, David M. [3 ,4 ]
Heierhorst, Joerg [1 ,2 ]
机构
[1] Univ Melbourne, St Vincents Inst Med Res, Melbourne, Vic 3052, Australia
[2] Univ Melbourne, Dept Med, Melbourne, Vic 3052, Australia
[3] Univ Melbourne, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia
[4] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3052, Australia
来源
JOURNAL OF EXPERIMENTAL MEDICINE | 2012年 / 209卷 / 09期
基金
英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
CLASS SWITCH RECOMBINATION; FAMILY-MEMBER BIM; DNA-DAMAGE; DYNEIN; DIFFERENTIATION; LYMPHOCYTES; CHAIN; LYMPHOPOIESIS; APOPTOSIS; SURVIVAL;
D O I
10.1084/jem.20120785
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Developing B lymphocytes expressing defective or autoreactive pre-B or B cell receptors (BCRs) are eliminated by programmed cell death, but how the balance between death and survival signals is regulated to prevent immunodeficiency and autoimmunity remains incompletely understood. In this study, we show that absence of the essential ATM (ataxia telangiectasia mutated) substrate Chk2-interacting Zn2+-finger protein (ASCIZ; also known as ATMIN/ZNF822), a protein with dual functions in the DNA damage response and as a transcription factor, leads to progressive cell loss from the pre-B stage onwards and severely diminished splenic B cell numbers in mice. This lymphopenia cannot be suppressed by deletion of p53 or complementation with a prearranged BCR, indicating that it is not caused by impaired DNA damage responses or defective V(D)J recombination. Instead, ASCIZ-deficient B cell precursors contain highly reduced levels of DYNLL1 (dynein light chain 1; LC8), a recently identified transcriptional target of ASCIZ, and normal B cell development can be restored by ectopic Dynll1 expression. Remarkably, the B cell lymphopenia in the absence of ASCIZ can also be fully suppressed by deletion of the proapoptotic DYNLL1 target Bim. Our findings demonstrate a key role for ASCIZ in regulating the survival of developing B cells by activating DYNLL1 expression, which may then modulate Bim-dependent apoptosis.
引用
收藏
页码:1629 / 1639
页数:11
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