St. Vincent's Institute of Medical Research, The University of Melbourne, Melbourne, Victoria 3052, Australia.
J Exp Med. 2012 Aug 27;209(9):1629-39. doi: 10.1084/jem.20120785. Epub 2012 Aug 13.
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 Zn(2+)-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.
表达缺陷或自身反应性前 B 或 B 细胞受体 (BCR) 的 B 淋巴细胞会通过程序性细胞死亡被清除，但死亡和存活信号之间的平衡如何被调节以防止免疫缺陷和自身免疫仍不完全清楚。在这项研究中，我们表明，缺乏必需的 ATM (ataxia telangiectasia mutated) 底物 Chk2 相互作用 Zn(2+) 指蛋白 (ASCIZ；也称为 ATMIN/ZNF822)，一种在 DNA 损伤反应和作为转录因子中具有双重功能的蛋白质，会导致前 B 阶段以来的细胞逐渐丢失，并导致小鼠脾脏 B 细胞数量严重减少。这种淋巴细胞减少不能通过 p53 的缺失或预先安排的 BCR 互补来抑制，表明它不是由 DNA 损伤反应受损或 V(D)J 重组缺陷引起的。相反，ASCIZ 缺陷的 B 细胞前体中含有高度降低的 DYNLL1（动力蛋白轻链 1；LC8）水平，DYNLL1 是 ASCIZ 的一个新鉴定的转录靶点，并且通过异位 Dynll1 表达可以恢复正常的 B 细胞发育。值得注意的是，缺乏 ASCIZ 时的 B 细胞淋巴细胞减少症也可以通过删除促凋亡的 DYNLL1 靶标 Bim 完全抑制。我们的研究结果表明，ASCIZ 通过激活 DYNLL1 表达在调节发育中的 B 细胞存活方面起着关键作用，这可能会调节 Bim 依赖性细胞凋亡。
