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.
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剪接调节剂通过从内含子翻译的易缩合蛋白引发全局翻译抑制。
DOI：
10.1016/j.chembiol.2021.07.015
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发表时间：
2022-02-17
影响因子：
8.6
通讯作者：
Yoshida M
中科院分区：
文献类型：
--
作者：
Chhipi-Shrestha JK;Schneider-Poetsch T;Suzuki T;Mito M;Khan K;Dohmae N;Iwasaki S;Yoshida M
与剪接体结合的化学剪接调节剂为癌症治疗提供了一条有吸引力的途径。剪接调节剂诱导内含子保留mrna子集的积累和随后的翻译。然而，含有翻译内含子序列的蛋白质的生物学效应尚不清楚。在这里，我们通过全基因组核糖体分析和生物正交非规范氨基酸标记（BONCAT）质谱鉴定了剪接调节剂spliceostatin a （SSA）处理后产生的许多截断蛋白。这些被截断的蛋白质的一个子集具有内在无序的区域，形成不溶性的细胞凝聚物，并通过JNK磷酸化触发蛋白质毒性应激反应，从而抑制mTORC1途径。反过来，这减少了全局转换。这些发现表明，从内含子中产生的易凝聚蛋白覆盖层抑制了翻译并阻止了有害截断蛋白的进一步产生。这一机制似乎有助于剪接调节剂的抗增殖和促凋亡活性。Chhipi-Shrestha等人表明，剪接调节导致保留内含子的广泛翻译，提供内在无序的蛋白质形成不溶性凝聚体并诱导细胞蛋白质毒性。激活的JNK抑制mTORC1通路，最终减少全局翻译，抑制有害截断蛋白的进一步产生。
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 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. Chhipi-Shrestha et al. show that splicing modulation leads to widespread translation from retained introns, supplying intrinsically disordered proteins to form insoluble condensates and to induce cellular proteotoxicity. Activated JNK inhibits the mTORC1 pathway and ultimately reduces the global translation, suppressing the further generation of harmful truncated proteins.
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影响因子：
10.5
作者：
Finci LI;Zhang X;Huang X;Zhou Q;Tsai J;Teng T;Agrawal A;Chan B;Irwin S;Karr C;Cook A;Zhu P;Reynolds D;Smith PG;Fekkes P;Buonamici S;Larsen NA
通讯作者：
Larsen NA
影响因子：
10.5
作者：
Boutz PL;Bhutkar A;Sharp PA
通讯作者：
Sharp PA
影响因子：
3.7
作者：
Koga M;Satoh T;Takasaki I;Kawamura Y;Yoshida M;Kaida D
通讯作者：
Kaida D
DOI：
10.1038/nrm.2017.27
发表时间：
2017-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baralle FE;Giudice J
通讯作者：
Giudice J
影响因子：
7.8
作者：
Adusumalli, Swarnaseetha;Ngian, Zhen-Kai;Ong, Chin-Tong
通讯作者：
Ong, Chin-Tong