USP8 Deubiquitinates the Leptin Receptor and Is Necessary for Leptin-Mediated Synapse Formation
USP8 Deubiquitinates the Leptin Receptor and Is Necessary for Leptin-Mediated Synapse Formation
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DOI：
10.1210/en.2019-00107
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发表时间：
2019-08-01
期刊：
影响因子：
4.8
通讯作者：
Wayman, Gary A.
中科院分区：
文献类型：
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作者：
Bland, Tyler;Sahin, Gulcan Semra;Wayman, Gary A.
瘦素在海马体中具有神经营养作用，可增加突触形成并刺激神经元可塑性。瘦素还可以增强认知能力，并具有抗抑郁和抗焦虑样作用，这是两种海马依赖性行为。相比之下，缺乏瘦素或长型瘦素受体（LepRb）的小鼠皮质体积较低，记忆力下降，并表现出抑郁样行为。许多受 LepRb 调节的信号通路是已知的，但中枢神经系统中膜 LepRb 水平如何调节尚不清楚。在这里，我们发现溶酶体抑制剂氯喹增加了海马培养物中 LepRb 的表达，表明 LepRb 在溶酶体中被降解。此外，我们发现瘦素通过降低泛素化 LepRb 的水平来增加其自身受体的表面表达。这种减少是由去泛素酶泛素特异性蛋白酶 8 (USP8) 介导的，我们证明它与 LepRb 形成复合物。急性瘦素刺激会增加 USP8 活性。此外，瘦素通过 cAMP 反应元件结合蛋白 (CREB) 依赖性转录刺激 USP8 基因表达，显性失活 CREB 的表达或 CREB 的短发夹 RNA 敲低可阻断这种效应。 USP8 表达增加导致 LepRb 表面定位增加，进而增强瘦素介导的 MAPK 激酶/细胞外信号调节激酶途径的激活和 CREB 激活。最后，USP8 表达增加会增加海马培养物中谷氨酸能突触的形成，这种效应依赖于 LepRbs 的表达。瘦素刺激的突触形成也需要 USP8。总之，我们表明 USP8 使 LepRb 去泛素化，从而抑制溶酶体降解并增强 LepRb 的表面定位，这对于瘦素刺激的海马突触发生至关重要。
Leptin has neurotrophic actions in the hippocampus to increase synapse formation and stimulate neuronal plasticity. Leptin also enhances cognition and has antidepressive and anxiolytic-like effects, two hippocampal-dependent behaviors. In contrast, mice lacking leptin or the long form of the leptin receptor (LepRb) have lower cortical volume and decreased memory and exhibit depressive-like behaviors. A number of the signaling pathways regulated by LepRb are known, but how membrane LepRb levels are regulated in the central nervous system is not well understood. Here, we show that the lysosomal inhibitor chloroquine increases LepRb expression in hippocampal cultures, suggesting that LepRb is degraded in the lysosome. Furthermore, we show that leptin increases surface expression of its own receptor by decreasing the level of ubiquitinated LepRbs. This decrease is mediated by the deubiquitinase ubiquitin-specific protease 8 (USP8), which we show is in complex with LepRb. Acute leptin stimulation increases USP8 activity. Moreover, leptin stimulates USP8 gene expression through cAMP response element-binding protein (CREB)-dependent transcription, an effect blocked by expression of a dominant-negative CREB or with short hairpin RNA knockdown of CREB. Increased expression of USP8 causes increased surface localization of LepRb, which in turn enhances leptin-mediated activation of the MAPK kinase/extracellular signal-regulated kinase pathway and CREB activation. Lastly, increased USP8 expression increases glutamatergic synapse formation in hippocampal cultures, an effect dependent on expression of LepRbs. Leptin-stimulated synapse formation also requires USP8. In conclusion, we show that USP8 deubiquitinates LepRb, thus inhibiting lysosomal degradation and enhancing surface localization of LepRb, which are essential for leptin-stimulated synaptogenesis in the hippocampus.