論文 - 詳細
| RRC ID | 68041 |
|---|---|
| 著者 | Chhipi-Shrestha JK, Schneider-Poetsch T, Suzuki T, Mito M, Khan K, Dohmae N, Iwasaki S, Yoshida M. |
| タイトル | Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns. |
| ジャーナル | Cell Chem Biol |
| Abstract |
Chemical splicing modulators that bind to the spliceosome have provided an attractive avenue for cancer treatment. Splicing modulators induce accumulation and subsequent translation of a subset of intron-retained mRNAs. However, the biological effect of proteins containing translated intron sequences remains unclear. Here, we identify a number of truncated proteins generated upon treatment with the splicing modulator spliceostatin A (SSA) via genome-wide ribosome profiling and bio-orthogonal noncanonical 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 c-Jun N-terminal kinase (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. |
| 巻・号 | 29(2) |
| ページ | 259-275.e10 |
| 公開日 | 2022-2-17 |
| DOI | 10.1016/j.chembiol.2021.07.015 |
| PII | S2451-9456(21)00355-X |
| PMID | 34520743 |
| PMC | PMC8857039 |
| MeSH | Cell Line Enzyme Inhibitors / pharmacology Humans Introns JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors JNK Mitogen-Activated Protein Kinases / genetics* Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors Mechanistic Target of Rapamycin Complex 1 / genetics* Pyrans / pharmacology RNA Splicing / drug effects RNA Splicing / genetics* RNA-Seq Spiro Compounds / pharmacology Spliceosomes / drug effects Spliceosomes / genetics* |
| IF | 6.762 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 25 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HeLa.S3(RCB1525) |