Dissection of pathways leading to antigen receptor-induced and Fas/CD95-induced apoptosis in human B cells.
Dissection of pathways leading to antigen receptor-induced and Fas/CD95-induced apoptosis in human B cells.
复制标题
剖析导致人类 B 细胞中抗原受体诱导和 Fas/CD95 诱导的细胞凋亡的途径。
作者：
S. Lens;B. D. den Drijver;A. Pötgens;K. Tesselaar;M. V. van Oers;R. V. van Lier
为了剖析参与B细胞Ag受体（BCR）介导和Fas诱导的人B细胞死亡的细胞内途径，我们分离了具有不同凋亡敏感性的伯基特淋巴瘤细胞系拉莫斯的克隆。对Fas诱导的细胞凋亡敏感性的选择也选择了具有增强的BCR死亡敏感性的克隆，反之亦然。相反，抗Fas介导的细胞凋亡的克隆仍然可以经历BCR诱导的细胞死亡。基于这些克隆的功能表型，我们假设这两种受体诱导的细胞凋亡途径最初是不同的，但最终可能会收敛。事实上，Fas和BCR的连接导致IL-1 β转化酶/Ced-3样蛋白酶半胱天冬酶3及其底物Ac-Asp-Glu-Val-Asp-醛和聚（ADP-核糖）聚合酶的裂解。明显地，观察到Fas或BCR连接诱导的caspase 3裂解模式的定性差异;而Fas连接产生19/20和17 kDa的caspase 3裂解产物，仅在BCR交联后发现后者裂解产物。半胱天冬酶抑制剂Val-Ala-Asp-fluoromethylketone阻断Fas和BCR介导的细胞凋亡，但差异影响由任一刺激诱导的半胱天冬酶3裂解。最后，发现Fas相关死亡结构域（FADD）显性负突变蛋白的过表达抑制Fas诱导的细胞凋亡，但不抑制BCR诱导的细胞凋亡。总之，我们的研究结果表明，Fas和BCR夫妇，通过FADD依赖和FADD独立的机制，分别到不同的蛋白酶上游的胱天蛋白酶3。
To dissect intracellular pathways involved in B cell Ag receptor (BCR)-mediated and Fas-induced human B cell death, we isolated clones of the Burkitt lymphoma cell line Ramos with different apoptosis sensitivities. Selection for sensitivity to Fas-induced apoptosis also selected for clones with enhanced BCR death sensitivity and vice versa. In contrast, clones resistant to Fas-mediated apoptosis could still undergo BCR-induced cell death. Based on the functional phenotypes of these clones, we hypothesized that both receptor-induced apoptosis pathways are initially distinct but may eventually converge. Indeed, ligation of both Fas and BCR resulted in cleavage of the IL-1beta-converting enzyme/Ced-3-like protease caspase 3 and its substrates Ac-Asp-Glu-Val-Asp-aldehyde and poly(ADP-ribose) polymerase. Markedly, qualitative differences in the caspase 3 cleavage pattern induced by Fas or BCR ligation were observed; whereas Fas ligation generated caspase 3 cleavage products of 19/20 and 17 kDa, only the latter cleavage product was found upon BCR cross-linking. The caspase inhibitor Val-Ala-Asp-fluoromethylketone blocked both Fas- and BCR-mediated apoptosis, but differentially affected caspase 3 cleavage induced by either stimulus. Finally, overexpression of a Fas-associated death domain (FADD) dominant-negative mutant protein was found to inhibit Fas-induced apoptosis but not BCR-induced apoptosis. Together our findings imply that Fas and BCR couple, via FADD-dependent and FADD-independent mechanisms, respectively, to distinct proteases upstream of caspase 3.
DOI：
10.1073/pnas.93.25.14486
发表时间：
1996-12-10
影响因子：
11.1
作者：
Srinivasula, SM;Ahmad, M;Alnemri, ES
通讯作者：
Alnemri, ES
IL-4 诱导 B 细胞中的 Fas 抵抗。
DOI：
--
发表时间：
1996
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Foote,LC;Howard,RG;Marshak-Rothstein,A;Rothstein,TL
通讯作者：
Rothstein,TL
影响因子：
4.2
作者：
Kinsella, TM;Nolan, GP
通讯作者：
Nolan, GP