Death Receptor Signaling

The death receptors (DR), all cell-surface receptors, that belong to the TNF receptor superfamily (TNFRSF). The term death receptor refers to those members of the TNFRSF that contain a "death domain" (DD) within their cytoplasmic tail which provides the capacity for protein–protein interactions with other DD-containing proteins suach as FADD. The main signals transmitted from TNF death receptors such as TNFR1, TRAIL-R, and CD95/FAS in response to their cognate ligand binding result in an apoptotic signaling pathway characterized by direct activation of intracellular cysteine proteases (caspases), without directly involving the mitochondrial death pathway. However, these death receptors have also been shown to initiate survival signals via the activation of transcription factors NFκappaB and AP1. This project describes an assembly of the death-inducing signaling complex (DISC) downstream of TNFR1, TRAIL-R, and CD95/FAS and shows protein composition and stoichiometry within the DISC. However, the DISC signaling complex may vary in its components stoichiometry. DR signaling may trigger formation of higher order receptor structures or signaling through rearrangement of receptor chains, which is not reflected here. The project also describes neuron-type-specific signaling by the p75NTR death receptor (also known as NGFR) that can regulate a number of different biological activities in response to ligand binding, including cell death and/or survival, axonal growth and synaptic plasticity.

死亡受体（DR）是一类细胞表面受体，属于肿瘤坏死因子受体超家族（TNFRSF）。‘死亡受体’一词特指那些在其细胞质尾部含有‘死亡结构域’（DD）的TNFRSF成员，此结构域赋予其与含有DD的其他蛋白质（如FADD）进行蛋白质-蛋白质相互作用的潜能。当TNF死亡受体如TNFR1、TRAIL-R和CD95/FAS与相应的配体结合时，主要传递的信号导致了一种以细胞内半胱氨酸蛋白酶（caspases）的直接激活为特征的凋亡信号通路，而不直接涉及线粒体死亡途径。然而，这些死亡受体也被证实可以通过激活转录因子NFκappaB和AP1来启动存活信号。本项目描述了TNFR1、TRAIL-R和CD95/FAS下游的死亡诱导信号复合物（DISC）的组装，并展示了DISC中的蛋白质组成和化学计量学。然而，DISC信号复合物的组分化学计量学可能存在差异。DR信号可能触发更高阶受体结构的形成或通过受体链的重排进行信号传导，但这在本描述中未予以体现。本项目还描述了p75NTR死亡受体（亦称NGFR）在神经元类型特异性信号传导中的作用，该受体在配体结合的刺激下，可以调节多种不同的生物学活动，包括细胞死亡和/或存活、轴突生长和突触可塑性等。