Proline rich结构域介导Nogo-A激活NF-κB信号

Nogo-A Activates NF-κB Through Its N-Terminal Proline Rich Domain

髓鞘来源的中枢神经再生抑制因子——Nogo-A被发现除表达于成熟的少突胶质细胞,还广泛高表达于多种类型的神经元中.目前,神经元中Nogo-A的功能还不明确.为探讨神经元内Nogo-A的功能,以HEK293FT细胞为模型,利用信号途径报告基因系统筛选过表达Nogo-A对多种信号途径的调控作用,发现过表达Nogo-A能特异激活NF-κB信号,利用不同的Nogo-A剪接体和截断体形式研究,证明Nogo-A激活NF-κB信号依赖于其氨基端的prolinerich结构域,进一步使用NF-κB信号途径相关分子显性突变体揭示IκBα、TRAF6、Rac/Cdc42参与Nogo-A激活NF-κB信号.结果提示,Nogo-A可以显著激活NF-κB信号,且依赖于Nogo-A氨基段的prolinerich结构域.

Nogo-A is a myelin derived neurite outgrowth inhibitor which is not only highly expressed in mature oligodendrocytes, but also in various kinds of neurons in the central nervous system. However, the function of neuronal Nogo-A remains unclear. To investigate the function of Nogo-A in neurons, human embryonic kidney cell line 293FT was used as a model, along with the pathway profiling reporter system to check the involvement of Nogo-A in regulating the intracellular signaling pathway. It was found that over-expression of Nogo-A could activate NF-κB signaling specifically, then followed by using different Nogo-A alternative splicing isoforms and a serial of truncations, it was confirmed that the activation of NF-κB by Nogo-A relied on its N-terminal proline rich domain. Furthermore, by co-expressing the dominant negative mutants of some NF-κB pathway associated proteins, it revealed that the IKBoL,TRAF6, Rac/Cdc42 were involved in Nogo-A inducing activation of NF-KB. Above all, these results indicate that Nogo-A could significantly activate NF-κB, and this activation depended primarily on its N-terminal proline rich domain.