NF-kappaB Cell Death Signaling

 描述（由申请人提供）：在视觉系统中，光的光子激活视紫红质启动称为光转导级联的事件链。该级联的失活通过调节蛋白抑制蛋白与视紫红质的结合在一个水平上实现。以前已经在果蝇中描述了感光细胞退化的机制，其中视紫红质和抑制蛋白之间的正常瞬时相互作用是稳定的。这些视紫红质/抑制蛋白复合物被内化到感光细胞的细胞体中，导致几乎所有视紫红质从横纹肌膜上丢失。视紫红质不被降解，而是作为不溶性聚集体积累在晚期内体中，最终导致感光细胞死亡。最近，我们已经确定，NF-κ B同源物Relish Dorsal和两种不同的先天免疫途径是这种形式的感光细胞变性所必需的。先天免疫途径是一种高度保守的信号传导途径，可保护细胞免受革兰氏阴性细菌感染。除了免疫信号传导之外，NF-kB是一种充分研究的转录因子，其还参与细胞增殖、炎症和细胞保护。由于NF-kB作为抗凋亡分子发挥作用，因此在果蝇视网膜中发现的细胞死亡诱导功能是新颖的。 在这份补助金中， 我们建议进一步研究NF-κ B在内吞作用介导的细胞死亡中的作用。这将通过旨在分离视网膜变性抑制因子的遗传筛选来实现。将选择一个抑制子子集用于未来研究。这项工作是第一次描述NF-kB信号被用于视网膜变性。

 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.