Luo Shiwen, Zhang Bin, Dong Xian-Ping, Tao Yanmei, Ting Annie, Zhou Zheng, Meixiong James, Luo Junjie, Chiu F C Alex, Xiong Wen C, Mei Lin
Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
Neuron. 2008 Oct 9;60(1):97-110. doi: 10.1016/j.neuron.2008.08.013.
Rapsyn, an acetylcholine receptor (AChR)-interacting protein, is essential for synapse formation at the neuromuscular junction (NMJ). Like many synaptic proteins, rapsyn turns over rapidly at synapses. However, little is known about molecular mechanisms that govern rapsyn stability. Using a differential mass-spectrometry approach, we identified heat-shock protein 90beta (HSP90beta) as a component in surface AChR clusters. The HSP90beta-AChR interaction required rapsyn and was stimulated by agrin. Inhibition of HSP90beta activity or expression, or disruption of its interaction with rapsyn attenuated agrin-induced formation of AChR clusters in vitro and impaired the development and maintenance of the NMJ in vivo. Finally, we showed that HSP90beta was necessary for rapsyn stabilization and regulated its proteasome-dependent degradation. Together, these results indicate a role of HSP90beta in NMJ development by regulating rapsyn turnover and subsequent AChR cluster formation and maintenance.
Rapsyn是一种与乙酰胆碱受体（AChR）相互作用的蛋白质，对神经肌肉接头（NMJ）处的突触形成至关重要。与许多突触蛋白一样，rapsyn在突触处迅速周转。然而，关于控制rapsyn稳定性的分子机制知之甚少。我们使用差异质谱分析法，确定热休克蛋白90β（HSP90β）是表面AChR簇中的一个成分。HSP90β与AChR的相互作用需要rapsyn，并受聚集蛋白刺激。抑制HSP90β的活性或表达，或破坏其与rapsyn的相互作用，会减弱聚集蛋白在体外诱导的AChR簇形成，并损害体内NMJ的发育和维持。最后，我们表明HSP90β对rapsyn的稳定是必需的，并调节其蛋白酶体依赖性降解。总之，这些结果表明HSP90β通过调节rapsyn周转以及随后的AChR簇形成和维持，在NMJ发育中发挥作用。
