Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns
Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns
Abstract Chemical splicing modulators that bind to the spliceosome have provided an attractive venue for cancer treatment. Splicing modulators induce accumulation and subsequent translation of a subset of intron-retained mRNAs. Yet, the biological effect of proteins containing translated intron sequences remains unclear. Here we identified a number of truncated proteins generated upon treatment with the splicing modulator spliceostatin A (SSA) using genome-wide ribosome profiling and bio-orthogonal non-canonical amino-acid tagging (BONCAT) mass spectrometry. A subset of these truncated proteins has intrinsically disordered regions, forms insoluble cellular condensates, and triggers the proteotoxic stress response through JNK phosphorylation, thereby inhibiting the mTORC1 pathway. In turn, this reduces global translation. These findings indicate that creating an overburden of condensate-prone proteins derived from introns represses translation and prevents further production of harmful truncated proteins. This mechanism appears to contribute to the antiproliferative and proapoptotic activity of splicing modulators.
Shrestha Jagat Krishna Chhipi、Schneider-Poetsch Tilman、Suzuki Takehiro、Mito Mari、Dohmae Naoshi、Yoshida Minoru、Khan Khalid、Iwasaki Shintaro
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science||Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of TokyoChemical Genomics Research Group, RIKEN Center for Sustainable Resource ScienceBiomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource ScienceRNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering ResearchBiomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource ScienceChemical Genomics Research Group, RIKEN Center for Sustainable Resource Science||Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo||Collaborative Research Institute for Innovative Microbiology, The University of TokyoChemical Genomics Research Group, RIKEN Center for Sustainable Resource ScienceRNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research||Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa||AMED-CREST, Japan Agency for Medical Research and Development
基础医学分子生物学生物化学
Shrestha Jagat Krishna Chhipi,Schneider-Poetsch Tilman,Suzuki Takehiro,Mito Mari,Dohmae Naoshi,Yoshida Minoru,Khan Khalid,Iwasaki Shintaro.Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns[EB/OL].(2025-03-28)[2025-05-21].https://www.biorxiv.org/content/10.1101/2020.11.23.393835.点此复制
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