在雷特综合征小鼠模型中，MeCP2 小泛素样修饰蛋白化可挽救 Mecp2 突变诱导的行为缺陷。
MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome.
作者信息
Tai Derek J C, Liu Yen C, Hsu Wei L, Ma Yun L, Cheng Sin J, Liu Shau Y, Lee Eminy H Y
机构信息
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.
出版信息
Nat Commun. 2016 Feb 4;7:10552. doi: 10.1038/ncomms10552.
The methyl-CpG-binding protein 2 (MeCP2) gene, MECP2, is an X-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). However, the molecular mechanism of MECP2-mutation-caused RTT is less known. Here we find that MeCP2 could be SUMO-modified by the E3 ligase PIAS1 at Lys-412. MeCP2 phosphorylation (at Ser-421 and Thr-308) facilitates MeCP2 SUMOylation, and MeCP2 SUMOylation is induced by NMDA, IGF-1 and CRF in the rat brain. MeCP2 SUMOylation releases CREB from the repressor complex and enhances Bdnf mRNA expression. Several MECP2 mutations identified in RTT patients show decreased MeCP2 SUMOylation. Re-expression of wild-type MeCP2 or SUMO-modified MeCP2 in Mecp2-null neurons rescues the deficits of social interaction, fear memory and LTP observed in Mecp2 conditional knockout (cKO) mice. These results together reveal an important role of MeCP2 SUMOylation in social interaction, memory and synaptic plasticity, and that abnormal MeCP2 SUMOylation is implicated in RTT.
甲基化CpG结合蛋白2（MeCP2）基因，即MECP2，是一个位于X染色体上的基因，负责编码MeCP2蛋白，MECP2的突变会导致雷特综合征（RTT）。然而，MECP2突变导致RTT的分子机制尚不清楚。在此，我们发现MeCP2可在赖氨酸412位点被E3连接酶PIAS1进行类泛素化修饰（SUMO修饰）。MeCP2的磷酸化（丝氨酸421和苏氨酸308位点）促进了MeCP2的SUMO化修饰，并且在大鼠大脑中，N-甲基-D-天冬氨酸（NMDA）、胰岛素样生长因子-1（IGF-1）和促肾上腺皮质激素释放因子（CRF）可诱导MeCP2的SUMO化修饰。MeCP2的SUMO化修饰使环磷腺苷效应元件结合蛋白（CREB）从抑制复合物中释放出来，并增强脑源性神经营养因子（Bdnf）mRNA的表达。在RTT患者中鉴定出的几种MECP2突变显示MeCP2的SUMO化修饰减少。在Mecp2基因敲除神经元中重新表达野生型MeCP2或SUMO修饰的MeCP2可挽救在Mecp2条件性敲除（cKO）小鼠中观察到的社交互动、恐惧记忆和长时程增强（LTP）缺陷。这些结果共同揭示了MeCP2的SUMO化修饰在社交互动、记忆和突触可塑性中的重要作用，并且异常的MeCP2 SUMO化修饰与RTT有关。
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