A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration  

作　　者：Dawei Meng Qian Zheng Xue Zhang Xuejiao Piao Li Luo Yichang Jia 

机构地区：[1]Tsinghua-Peking Joint Center for Life Sciences,Tsinghua University,Beijing 100084,China [2]School of Life Sciences,Tsinghua University,Beijing 100084,China [3]School of Medicine,Tsinghua University,Beijing 100084,China [4]IDG/McGovern Institute for Brain Research,Tsinghua University,Beijing 100084,China [5]Tsinghua Laboratory of Brain and Intelligence,Tsinghua University,Beijing 100084,China

出　　处：《Protein & Cell》2023年第5期318-336,共19页蛋白质与细胞（英文版）

基　　金：the Tsinghua-Peking Joint Center for Life Sciences,the Thousand-Talent Young Investigator Program,the IDG/McGovern Institute for Brain Research,the National Natural Science Foundation of China(81371361,92049114,31571097,82101495);The Beijing Municipal Science&Technology Commission(Z181100001518001,Z161100000216154);National Key R&D Program(2017YFC0110205);the Institute for Guo Qiang,Tsinghua University。

摘　　要：Emerging evidence suggests that intron-detaining transcripts(IDTs)are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress.However,the underlying mechanisms of detained intron(DI)splicing are still largely unknown.Here,we suggest that post-transcriptional DI splicing is paused at the Bact state,an active spliceosome but not catalytically primed,which depends on Smad Nuclear Interacting Protein 1(SNIP1)and RNPS1(a serine-rich RNA binding protein)interaction.RNPS1 and Bact components preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing.Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA,a basal spliceosomal component.Snip1 conditional knockout in the cerebellum decreases DI splicing efficiency and causes neurodegeneration.Therefore,we suggest that SNIP1 and RNPS1 form a molecular brake to promote spliceosome pausing,and that its misregulation contributes to neurodegeneration.

关 键 词：SNIP1 RNPS1 SPLICEOSOME detained intron NEURODEGENERATION 

分 类 号：Q75[生物学—分子生物学]