NF-kappaB Cell Death Signaling

 描述(申请人提供)：在视觉系统中，光的光子激活视紫红质启动了一系列称为光转导级联的事件。这一级联反应的失活是通过调节蛋白arrestin与视紫红质的结合在一个水平上实现的。在果蝇中，光感受器细胞退化的机制已经被描述，其中视紫红质和arrestin之间正常的瞬时相互作用是稳定的。这些视紫红质/arrestin复合体被内化到感光细胞的细胞体中，导致横纹膜上几乎所有的视紫红质丢失。视紫红质不会被降解，而是以不溶性聚集体的形式积累在晚期的内体中，最终导致光感受器细胞死亡。最近，我们确定了这种类型的感光细胞退化所必需的两条不同的天然免疫途径。先天免疫通路是一种高度保守的信号通路，可以保护细胞免受革兰氏阴性细菌的感染。除了免疫信号外，核因子-kB也是一种被广泛研究的转录因子，它还参与细胞增殖、炎症和细胞保护。由于核因子-kB是一种抗凋亡分子，因此在果蝇视网膜中发现的诱导细胞死亡的功能是新的。在这笔赠款中， 我们建议进一步研究核因子-kB在内吞作用介导的细胞死亡中的作用。这将通过一种旨在分离视网膜变性抑制因子的基因筛查来实现。将选择抑制基因的一个子集用于未来的研究。这项工作是第一次描述核因子-kB信号在视网膜变性中的应用。

 DESCRIPTION (provided by applicant): In the visual system, the activation of rhodopsin by a photon of light initiates a chain of events referred to as the photo transduction cascade. The inactivation of this cascade is achieved at one level by the binding of the regulatory protein arrestin to rhodopsin. A mechanism of photoreceptor cell degeneration has previously been described in Drosophila where the normally transient interaction between rhodopsin and arrestin is stabilized. These rhodopsin/arrestin complexes are internalized into the cell body of the photoreceptor cell resulting in the loss of nearly all rhodopsin from the rhabdomeric membrane. The rhodopsin is not degraded but instead accumulates in the late endosome as insoluble aggregates, eventually leading to photoreceptor cell death. Recently we have determined that the NF-kB homologues Relish Dorsal and two different innate immunity pathways are necessary for this form of photoreceptor cell degeneration. The innate immunity pathway is a highly conserved signaling pathway that protects cells from gram-negative bacterial infection. In addition to immunity signaling, NF-kB is a well-studied transcription factor that is also involved n cell proliferation, inflammation, and cell protection. Since NF-kB functions as an antiapoptotic molecule, the cell death inducing function found in the Drosophila retina is novel. In this grant, we propose to further investigate the role of NF-kB in endocytosis-mediated cell death. This will be accomplished by a genetic screen aimed at isolating suppressors of retinal degeneration. A subset of the suppressors will be selected for future study. This work is the first description of NF-kB signaling being utilized in retinal degeneration.