MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome

• Published in: Nature communications Vol. 7; no. 1; p. 10552
• Main Authors: Tai, Derek J. C., Liu, Yen C., Hsu, Wei L., Ma, Yun L., Cheng, Sin J., Liu, Shau Y., Lee, Eminy H. Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/19; 38; 38/1; 38/109; 38/23; 38/70; 38/77; 38/89; 631/337/458/538; 631/378/1689; 82; 82/51; 82/58; 82/83; 96; 96/106; Amino acids; Animals; Autism; Behavior, Animal; Blotting, Western; Brain; Brain-derived neurotrophic factor; CA1 Region, Hippocampal - metabolism; Disease Models, Animal; Exploratory Behavior; Fear; Gene Knockout Techniques; Genetic Vectors; Hippocampus - metabolism; Humanities and Social Sciences; Immunohistochemistry; Immunoprecipitation; In Vitro Techniques; Learning; Lentivirus; Memory; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; multidisciplinary; Mutagenesis, Site-Directed; Mutation; Neuronal Plasticity; Neurons - metabolism; Phosphorylation; Protein Inhibitors of Activated STAT - metabolism; Proteins; Rats; Rats, Sprague-Dawley; Rett Syndrome - genetics; Rett Syndrome - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Science; Science (multidisciplinary); Social Behavior; Social interaction; Sumoylation; Taiwan
• ISSN: 2041-1723; 2041-1723
• 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 ME CP2 -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. Post-translational modifications of methyl-CpG-binding protein 2 (MeCP2) are important for its function and dysfunction in Rett syndrome. Here, Tai et al . show a functional interaction between MeCP2 SUMOylation and phosphorylation in rodent behavior and synaptic plasticity.