Synaptotagmin-11 (Syt11) is associated with schizophrenia and Parkinson’s disease (PD) and is a critical substrate of parkin, an E3 ubiquitin ligase linked to PD. Previously we reported that Syt11 regulates multiple membrane trafficking pathways in neurons and glia. However, the regulation of Syt11 degradation remains largely unknown. As the ubiquitin-proteasome pathway (UPP) plays crucial roles in protein degradation and quality control, we investigated UPP-dependent Syt11 degradation in this study. We found that Syt11 is a short-lived protein with a half-life of 1.49 h in the presence of a protein synthesis inhibitor cycloheximide and is mainly degraded by UPP in neurons. The degradation was further accelerated under sustained neuronal activity and was parkin-dependent. Interestingly, Syt11 had a faster turnover in astrocytes with a half-life of 0.58 h, and UPP partially contributed to its degradation. Mechanical stress applied on astrocytes by hypoosmotic treatment led to reduced Syt11 protein level but increased parkin level. However, the degradation of Syt11 was parkin-independent under both isoosmotic and hypoosmotic condition. Altogether, our results revealed active and distinct proteolytic regulation of Syt11 in neurons and astrocytes.

Synaptotagmin-11（Syt11）与精神分裂症和帕金森氏病（PD）相关，并且是帕金的关键底物，帕金是与PD相连的E3泛素连接酶。以前我们报道过Syt11调节神经元和神经胶质中的多个膜运输途径。但是，Syt11降解的调控仍然很大程度上未知。由于泛素-蛋白酶体途径（UPP）在蛋白质降解和质量控制中起着至关重要的作用，因此我们在本研究中研究了UPP依赖性Syt11降解。我们发现Syt11是一种短暂的蛋白质，在蛋白质合成抑制剂环己酰亚胺的存在下半衰期为1.49小时，并且主要被神经元中的UPP降解。在持续的神经元活性下，降解进一步加速并且是帕金依赖性的。有趣的是 Syt11在星形胶质细胞中具有更快的周转率，半衰期为0.58 h，UPP对其降解有部分贡献。低渗处理对星形胶质细胞施加的机械应力导致Syt11蛋白水平降低，但帕金蛋白水平升高。然而，在等渗和低渗条件下，Syt11的降解均不依赖于Parkin。总之，我们的结果显示了神经元和星形胶质细胞中Syt11的活跃而独特的蛋白水解调控。