Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China.
Department of Neurobiology, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Capital Medical University, Beijing, China.
FASEB J. 2020 Feb;34(2):2609-2624. doi: 10.1096/fj.201901715R. Epub 2019 Dec 20.
Caveolae play crucial roles in intracellular membrane trafficking and mechanosensation. In this study, we report that synaptotagmin-11 (Syt11), a synaptotagmin isoform associated with Parkinson's disease and schizophrenia, regulates both caveolae-mediated endocytosis and the caveolar response to mechanical stimuli in astrocytes. Syt11-knockout (KO) accelerated caveolae-mediated endocytosis. Interestingly, the caveolar structures on the cell surface were markedly fewer in the absence of Syt11. Caveolar disassembly in response to hypoosmotic stimuli and astrocyte swelling were both impaired in Syt11-KO astrocytes. Live imaging revealed that Syt11 left caveolar structures before cavin1 during hypoosmotic stress and returned earlier than cavin1 after isoosmotic recovery. Chronic hypoosmotic stress led to proteasome-mediated Syt11 degradation. In addition, Syt11-KO increased the turnover of cavin1 and EH domain-containing protein 2 (EHD2), accompanied by compromised membrane integrity, suggesting a mechanoprotective role of Syt11. Direct interactions between Syt11 and cavin1 and EHD2, but not caveolin-1, are found. Altogether, we propose that Syt11 stabilizes caveolar structures on the cell surface of astrocytes and regulates caveolar functions under physiological and pathological conditions through cavin1 and EHD2.
小窝在细胞内膜运输和机械感觉中起着至关重要的作用。在这项研究中，我们报告了突触结合蛋白 11（Syt11），一种与帕金森病和精神分裂症相关的突触结合蛋白异构体，调节星形胶质细胞中小窝介导的内吞作用和小窝对机械刺激的反应。Syt11 敲除（KO）加速了小窝介导的内吞作用。有趣的是，在没有 Syt11 的情况下，细胞表面的小窝结构明显减少。Syt11-KO 星形胶质细胞对低渗刺激引起的小窝解组装和细胞肿胀反应均受损。实时成像显示，在低渗应激下，Syt11 先于 cavin1 离开小窝结构，在等渗恢复后比 cavin1 更早返回。慢性低渗应激导致蛋白酶体介导的 Syt11 降解。此外，Syt11-KO 增加了 cavin1 和 EH 结构域包含蛋白 2（EHD2）的周转率，同时伴有膜完整性受损，表明 Syt11 具有机械保护作用。发现 Syt11 与 cavin1 和 EHD2 之间存在直接相互作用，但与 caveolin-1 之间没有相互作用。总之，我们提出 Syt11 通过 cavin1 和 EHD2 稳定星形胶质细胞膜表面的小窝结构，并调节生理和病理条件下的小窝功能。
