Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD

• 成果类型: Article
• 署名作者: Garcia-Cabau, Carla; Bartomeu, Anna; Tesei, Giulio; Cheung, Kai Chit; Pose-Utrilla, Julia; Pico, Sara; Balaceanu, Andreea; Duran-Arque, Berta; Fernandez-Alfara, Marcos; Martin, Judit; De Pace, Cesare; Ruiz-Perez, Lorena; Garcia, Jesus; Battaglia, Giuseppe; Lucas, Jose J.; Hervas, Ruben; Lindorff-Larsen, Kresten; Mendez, Raul; Salvatella, Xavier
• 署名单位: Barcelona Institute of Science & Technology; Institute for Research in Biomedicine - IRB Barcelona; University of Copenhagen; University of Hong Kong; Autonomous University of Madrid; Consejo Superior de Investigaciones Cientificas (CSIC); Instituto de Salud Carlos III; University of London; University College London; University of London; University College London; Barcelona Institute of Science & Technology; Institut de Bioenginyeria de Catalunya; University of Barcelona; University of Barcelona; ICREA
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3456
• DOI: 10.1038/s41586-024-08289-w
• 发表日期: 2025-01-09
• 页码: 496-+
• 关键词: intrinsically disordered proteins; solid-phase-transition; SEPARATION; mechanism; nmr; polyadenylation; DYNAMICS; BEHAVIOR; liquid; ph

摘要

The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders(1). We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD)(2). Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.