Department of Chemistry, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
Department of Chemistry, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Mar;1865(3):158608. doi: 10.1016/j.bbalip.2019.158608. Epub 2019 Dec 28.
Brain-specific diacylglycerol kinase (DGK) δ-knockout mice exhibited serotonin transporter (SERT) inhibitor-sensitive obsessive-compulsive disorder-like behaviors. Moreover, SERT protein levels were markedly increased in the DGKδ-deficient brain. However, its molecular mechanisms remain unclear. We found that the catalytic subdomain-a and the coiled-coil structure-containing region of DGKδ interacted with the C-terminal cytoplasmic region (CTC) of SERT. Moreover, the protein levels of full-length SERT and SERT-CTC alone were significantly decreased by DGKδ in a catalytic activity-dependent manner. A proteasome inhibitor, MG-132, inhibited DGKδ-dependent SERT degradation. Notably, DGKδ interacted with MAGE-D1 adaptor protein and Praja-1 E3 ubiquitin-protein ligase, and enhanced the ubiquitination of SERT through Praja-1. Taken together, these results indicate that DGKδ interacts with SERT and induces SERT degradation in an activity-dependent manner through the Praja-1 ubiquitin ligase-proteasome system. These new findings provide novel insights into serotonergic system regulation and the pathophysiology/therapeutics of serotonin-/SERT-related diseases such as obsessive-compulsive disorder, depression, autism and schizophrenia.
脑特异性二酰基甘油激酶 (DGK) δ 敲除小鼠表现出 5-羟色胺转运体 (SERT) 抑制剂敏感的强迫症样行为。此外，DGKδ 缺陷大脑中的 SERT 蛋白水平显著增加。然而，其分子机制尚不清楚。我们发现 DGKδ 的催化亚基-a 和富含卷曲螺旋结构的区域与 SERT 的 C 端胞质区 (CTC) 相互作用。此外，全长 SERT 和 SERT-CTC 的蛋白水平均显著降低，这一过程依赖于 DGKδ 的催化活性。蛋白酶体抑制剂 MG-132 抑制了 DGKδ 依赖的 SERT 降解。值得注意的是，DGKδ 与 MAGE-D1 衔接蛋白和 Praja-1 E3 泛素连接酶相互作用，并通过 Praja-1 增强 SERT 的泛素化。总之，这些结果表明，DGKδ 通过 Praja-1 泛素连接酶-蛋白酶体系统与 SERT 相互作用，并以依赖活性的方式诱导 SERT 降解。这些新发现为 5-羟色胺能系统调节以及与 5-羟色胺/SERT 相关疾病（如强迫症、抑郁症、自闭症和精神分裂症）的病理生理学/治疗学提供了新的见解。
