Lee Kyeong-Hee, Feig Christine, Tchikov Vladimir, Schickel Robert, Hallas Cora, Schütze Stefan, Peter Marcus E, Chan Andrew C
Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
EMBO J. 2006 Mar 8;25(5):1009-23. doi: 10.1038/sj.emboj.7601016. Epub 2006 Feb 23.
Activation of the cell surface CD95 receptor triggers a cascade of signaling events, including assembly of the death-inducing signaling complex (DISC), that culminate in cellular apoptosis. In this study, we demonstrate a general requirement of receptor internalization for CD95 ligand-mediated DISC amplification, caspase activation and apoptosis in type I cells. Recruitment of DISC components to the activated receptor predominantly occurs after the receptor has moved into an endosomal compartment and blockade of CD95 internalization impairs DISC formation and apoptosis. In contrast, CD95 ligand stimulation of cells unable to internalize CD95 results in activation of proliferative Erk and NF-kappaB signaling pathways. Hence, the subcellular localization and internalization pathways of CD95 play important roles in controlling activation of distinct signaling cascades to determine divergent cellular fates.
细胞表面CD95受体的激活引发了一系列信号事件，包括死亡诱导信号复合物（DISC）的组装，最终导致细胞凋亡。在本研究中，我们证明了I型细胞中受体内化对于CD95配体介导的DISC扩增、半胱天冬酶激活和细胞凋亡的普遍需求。DISC组分募集到活化受体主要发生在受体进入内体区室之后，并且阻断CD95内化会损害DISC形成和细胞凋亡。相反，CD95配体刺激无法内化CD95的细胞会导致增殖性Erk和NF-κB信号通路的激活。因此，CD95的亚细胞定位和内化途径在控制不同信号级联的激活以决定不同细胞命运方面发挥着重要作用。
