Cell Biology of Signaling By TNF Receptors

TNF 受体信号传导的细胞生物学

• 批准号: 6823125
• 负责人: Richard M Siegel
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6823125
• 关键词: CD95 molecule; apoptosis; biological signal transduction; cysteine endopeptidases; growth factor receptors; human tissue; immunoregulation; ligands; membrane structure; molecular assembly /self assembly; protein localization; protein structure function; receptor binding; receptor mediated endocytosis; tissue /cell culture; tumor necrosis factor alpha

TNF ligand-receptor interactions serve diverse functions in immune system regulation. Fas, a member of the TNF receptor family is an important regulator of lymphocyte homeostasis and can cause systemic autoimmunity when genetically mutated. Althuogh a number of signaling proteins mediating TNF receptor signals have been identified, the cell biology of receptor signaling: where signaling events take place within the cell and whether subcellular localization plays a role in regulating TNF receptor signaling, remains relatively unknown. Understanding of this process is important for devising better ways to modulate signaling through these receptors for therapeutic goals. In previous work, we established that TNF receptors must pre-associate into mutimeric complexes to signal efficiently. Preassociation of Fas and TNFR1 is mediated by an N-terminal pre-ligand association domain (PLAD). We are currently investigating whether adding bacterially synthesized PLAD domain fragments can bind to native receptors and inhibit their function. For the apoptosis-inducing receptor Fas (CD95, APO-1), we have more recently characterized much larger microscopically visible surface receptor clusters initiated by antibody or ligand that are dependent on the death domain and are required for caspase-8 activation and apoptosis signaling. Additionally, we have found a role for lipid raft microdomains in regulating the efficiency of Fas signaling.

TNF配体 - 受体相互作用在免疫系统调节中起多种功能。 FAS是TNF受体家族的成员是淋巴细胞稳态的重要调节剂，当遗传突变时会引起全身自身免疫性。已经鉴定出许多介导TNF受体信号的信号蛋白，受体信号传导的细胞生物学：信号事件发生在细胞内，以及亚细胞定位是否在调节TNF受体信号传导中起作用，仍然相对尚不清楚。理解此过程对于设计更好的方法来通过这些受体调节信号传导以实现治疗目标很重要。在先前的工作中，我们确定TNF受体必须预先缔合成企业复合物，以有效发信号。 FA和TNFR1的预邻化是由N末端的凸固体结合域（PLAD）介导的。我们目前正在研究添加细菌合成的plad结构域片段是否可以与天然受体结合并抑制其功能。对于诱导凋亡的受体FA（CD95，APO-1），我们最近表征了依赖于死亡结构域的抗体或配体引发的显微镜可见的表面受体簇，并且是caspase-8激活和凋亡信号传导所必需的。此外，我们发现脂质筏微域在调节FAS信号的效率中起作用。