Gandu Srinivasa R, Rodriguez Ana R, Lamp Jared, Patel Mihir V, Madura Kiran, Vega Irving E, Firestein Bonnie L
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA.
Cell and Developmental Biology Graduate Program, Rutgers University, Piscataway, NJ, USA.
Sci Adv. 2025 Jul 11;11(28):eads5467. doi: 10.1126/sciadv.ads5467.
An open question in neuroscience is how protein posttranslational modifications regulate synaptic site targeting. Polyubiquitination plays a role in proteasome-mediated protein turnover; however, additional functions for specific types of polyubiquitin linkages have been identified. One type of polyubiquitination, K63-polyubiquitin (K63-polyUb), has been studied for its role in signal transduction within the context of cancer, but little has been done to uncover its role regarding neuronal and synaptic function. Here, we report an emerging function for the cytosolic PSD-95 interactor, cypin, in the regulation of synaptic content by K63-polyUb during neuronal development in vitro and in adult mice in vivo. We identify cypin-promoted K63-polyUb on postsynaptic proteins and also find an important role for cypin in presynaptic function. Our work demonstrates that cypin-promoted changes to K63-polyUb can regulate synaptic content and function on both sides of the synapse, adding important insight into basic mechanisms of neuronal signaling.
神经科学中一个尚未解决的问题是蛋白质翻译后修饰如何调节突触位点靶向。多聚泛素化在蛋白酶体介导的蛋白质周转中起作用；然而，已确定特定类型的多聚泛素连接具有其他功能。一种多聚泛素化类型，即K63-多聚泛素（K63-polyUb），已在癌症背景下对其在信号转导中的作用进行了研究，但在揭示其在神经元和突触功能方面的作用方面做得很少。在这里，我们报告了一种胞质PSD-95相互作用蛋白cypin在体外神经元发育和成年小鼠体内通过K63-多聚泛素调节突触含量方面的新功能。我们鉴定出cypin促进突触后蛋白上的K63-多聚泛素化，并且还发现cypin在突触前功能中起重要作用。我们的工作表明，cypin促进的K63-多聚泛素化变化可以调节突触两侧的突触含量和功能，为神经元信号传导的基本机制提供了重要见解。
