The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim.
The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim.
复制标题
DOI：
10.1084/jem.20120785
复制
发表时间：
2012-08-27
期刊：
影响因子：
--
通讯作者：
Heierhorst J
中科院分区：
文献类型：
--
作者：
Jurado S;Gleeson K;O'Donnell K;Izon DJ;Walkley CR;Strasser A;Tarlinton DM;Heierhorst J
B细胞发育需要锌指蛋白和ATM底物ASCIZ通过DYNLL 1和Bim发出信号。发育中的B淋巴细胞表达有缺陷的或自身反应性的前B或B细胞受体（BCR），通过程序性细胞死亡被消除，但是如何调节死亡和存活信号之间的平衡以防止免疫缺陷和自身免疫仍然不完全清楚。在这项研究中，我们表明，缺乏必要的ATM（共济失调毛细血管扩张症突变）底物Chk 2相互作用锌2+指蛋白（ASCIZ;也称为ATMIN/ZNF 822），在DNA损伤反应和作为转录因子的双重功能的蛋白质，导致进行性细胞损失从前B阶段向前和严重减少脾脏B细胞数量在小鼠。这种淋巴细胞减少症不能通过缺失p53或与预先排列的BCR互补来抑制，表明它不是由受损的DNA损伤反应或缺陷的V（D）J重组引起的。相反，ASCIZ缺陷型B细胞前体含有高度降低水平的DYNLL 1（动力蛋白轻链1; LC 8），DYNLL 1是最近鉴定的ASCIZ的转录靶，并且正常的B细胞发育可以通过异位DynLL 1表达来恢复。值得注意的是，在不存在ASCIZ的情况下，B细胞淋巴细胞减少症也可以通过缺失促凋亡DYNLL 1靶标Bim而被完全抑制。我们的研究结果表明，ASCIZ通过激活DYNLL 1的表达，从而调节Bim依赖性凋亡，在调节发育中的B细胞的存活中发挥关键作用。
B cell development requires the Zinc-finger protein and ATM substrate ASCIZ to signal through DYNLL1 and Bim. 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.
登录
查看更多内容
影响因子：
4.8
作者：
Jurado, Sabine;Conlan, Lindus A.;Heierhorst, Joerg
通讯作者：
Heierhorst, Joerg
影响因子：
56.9
作者：
OETTINGER, MA;SCHATZ, DG;BALTIMORE, D
通讯作者：
BALTIMORE, D
影响因子：
4.8
作者：
Kanu, Nnennaya;Penicud, Kay;Behrens, Axel
通讯作者：
Behrens, Axel
DOI：
10.1073/pnas.90.18.8392
发表时间：
1993-09-15
影响因子：
11.1
作者：
PEAR, WS;NOLAN, GP;BALTIMORE, D
通讯作者：
BALTIMORE, D
影响因子：
4.3
作者：
Heierhorst, Joerg;Smyth, Ian;Jurado, Sabine
通讯作者：
Jurado, Sabine