PDF(Pubmed)
Abstract：
Current models posit that nuclear speckles (NSs) serve as reservoirs of splicing factors and facilitate posttranscriptional mRNA processing. Here, we discovered that ribotoxic stress induces a profound reorganization of NSs with enhanced recruitment of factors required for splice-site recognition, including the RNA-binding protein TIAR, U1 snRNP proteins and U2-associated factor 65, as well as serine 2 phosphorylated RNA polymerase II. NS reorganization relies on the stress-activated p38 mitogen-activated protein kinase (MAPK) pathway and coincides with splicing activation of both pre-existing and newly synthesized pre-mRNAs. In particular, ribotoxic stress causes targeted excision of retained introns from pre-mRNAs of immediate early genes (IEGs), whose transcription is induced during the stress response. Importantly, enhanced splicing of the IEGs ZFP36 and FOS is accompanied by relocalization of the corresponding nuclear mRNA foci to NSs. Our study reveals NSs as a dynamic compartment that is remodeled under stress conditions, whereby NSs appear to become sites of IEG transcription and efficient cotranscriptional splicing.
摘要：
目前的模型认为核斑点（NSs）是剪接因子的储库，并促进转录后mRNA的加工。这里,我们发现利波毒性应激诱导了NSs的深刻重组，增强了剪接位点识别所需的因子的募集，包括RNA结合蛋白TIAR，U1snRNP蛋白和U2相关因子65，以及丝氨酸2磷酸化RNA聚合酶II。NS重组依赖于应激激活的p38丝裂原激活的蛋白激酶（MAPK）途径，并且与先前存在的和新合成的前mRNA的剪接激活一致。特别是,利波毒性应激导致从立即早期基因（IEGs）的前mRNA中靶向切除保留的内含子，其转录在应激反应期间被诱导。重要的是,IEGZFP36和FOS的增强剪接伴随着相应的核mRNA病灶重新定位到NSs。我们的研究揭示了NS作为一个动态隔室，在应力条件下被重塑，其中NSs似乎成为IEG转录和有效的共转录剪接的位点。
