The Death Domain of FADD Is Essential for Embryogenesis, Lymphocyte Development, and Proliferation
The Death Domain of FADD Is Essential for Embryogenesis, Lymphocyte Development, and Proliferation
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DOI：
10.1074/jbc.m900249200
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发表时间：
2009-04-10
影响因子：
4.8
通讯作者：
Zhang, Jianke
中科院分区：
文献类型：
--
作者：
Imtiyaz, Hongxia Z.;Zhou, Xiaohui;Zhang, Jianke
Fas相关死亡结构域蛋白（FADD）是一种衔接子，用于传递由死亡受体（如Fas）启动的凋亡信号。而缺乏死亡受体对小鼠发育没有影响，FADD缺陷导致早期胚胎死亡，表明FADD具有独立于死亡受体的额外功能。我们以前已经表明，FADD的条件性缺失不仅损害细胞凋亡，而且导致淋巴细胞增殖缺陷。FADD介导的非凋亡信号传导仍然知之甚少。早期的研究表明，FADD羧基末端丝氨酸磷酸化可能在T细胞中FADD介导的增殖信号中起作用。FADD死亡结构域可能仅是凋亡信号传导所需的，因为它与在胚胎发育和淋巴细胞增殖期间被激活的死亡受体相互作用。为了验证这一假设，我们进行了突变分析的FADD死亡结构域，并确定了突变体，R117 Q，它缺乏结合Fas，因此，是不能在细胞系中的凋亡信号。出乎意料的是，这种死亡结构域点突变破坏了小鼠胚胎发育，如体内功能重建分析所示。有趣的是，第二个FADD死亡结构域突变体V121 N保留了正常的Fas结合和凋亡信号传导能力，但也未能支持小鼠发育。此外，淋巴细胞增殖反应被V121N损害。这项反向遗传学研究揭示了FADD死亡结构域以前未被重视的作用，它可能作为调节两种不同信号的分子开关，导致细胞凋亡和细胞增殖，对胚胎发生，淋巴细胞发育和增殖至关重要。
The Fas-associated death domain-containing protein ( FADD) is an adaptor for relaying apoptotic signals initiated by death receptors such as Fas. Whereas a lack of death receptors has no effect on mouse development, FADD deficiency results in early embryonic lethality, indicating that FADD has additional functions independent of death receptors. We have previously shown that conditional deletion of FADD not only impairs apoptosis but also leads to defective lymphocyte proliferation. The non-apoptotic signaling mediated by FADD remains poorly understood. Earlier studies have suggested that FADD carboxyl terminal serine phosphorylation likely plays a role in FADD-mediated proliferation signaling in T cells. The FADD death domain is presumably only required for apoptotic signaling, as it interacts with death receptors which are dispensable during embryonic development and lymphocyte proliferation. To test this hypothesis, we have performed mutational analyses of the FADD death domain and identified a mutant, R117Q, which lacks binding to Fas and, thus, is incapable of apoptotic signaling in cell lines. Unexpectedly, this death domain point mutation disrupted mouse embryonic development as shown by in vivo functional reconstitution analyses. Interestingly, a second FADD death domain mutant, V121N, retained normal Fas binding and apoptotic signaling ability but also failed to support mouse development. Furthermore, lymphocyte proliferation responses were impaired by V121N. This reverse genetic study has revealed a previously unappreciated role of the FADD death domain, which likely functions as a molecular switch regulating two distinct signals leading to apoptosis and cell proliferation and is critical for embryogenesis, lymphocyte development, and proliferation.