Department of Chemistry, University of California Riverside, Riverside, CA, 92521-0403, USA.
Department of Botany and Plant Sciences, University of California Riverside, Riverside, CA, 92521-0403, USA.
Nat Commun. 2019 Aug 9;10(1):3613. doi: 10.1038/s41467-019-11552-8.
Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N-methyladenosine (mA). Furthermore, exposure to ganetespib leads to elevated modification levels at mA motif sites in the 5'-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5'-UTR promotes the translation of the reporter gene mRNA. This mA-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism.
小分子抑制剂已被广泛用于 90kDa 热休克蛋白（HSP90）的临床前研究，以治疗伴有蛋白毒性应激的人类疾病。通过使用无偏定量蛋白质组学方法，我们发现三种 HSP90 抑制剂的治疗导致大量热休克蛋白的表达升高。我们还证明 HSP90 抑制剂介导的 DNAJB4 蛋白表达增加部分是通过转录后修饰机制发生的，并且受到 N6-甲基腺苷（m6A）的写入器、擦除器和读取器蛋白的显著调节。此外，加尼替塞治疗导致 DNAJB4 mRNA 5'UTR 中的 m6A 修饰位点修饰水平升高，并且 5'UTR 中腺苷 114 位的甲基化促进报告基因 mRNA 的翻译。这种 m6A 介导的机制在热休克处理时也起作用。总之，我们揭示 HSP90 抑制剂通过转录后修饰机制刺激 DNAJB4 的翻译。
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