Diphthamide promotes TOR signaling by increasing the translation of proteins in the TORC1 pathway.
Diphthamide promotes TOR signaling by increasing the translation of proteins in the TORC1 pathway.
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DOI：
10.1073/pnas.2104577118
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发表时间：
2021-09-14
影响因子：
11.1
通讯作者：
Lin H
中科院分区：
文献类型：
--
作者：
Zhang Y;Lin Z;Zhu J;Wang M;Lin H
Diphthamide 是一种自 20 世纪 70 年代以来就为人所知的翻译后修饰。它在所有真核细胞中都是保守的，其生物合成至少需要七种蛋白质。然而，其确切的生物学功能仍不清楚。我们的结果表明，diphthamide 通过促进雷帕霉素复合物 1 (TORC1) 靶标途径中两种蛋白质的翻译来促进雷帕霉素靶标 (TOR) 信号转导，这两种蛋白质的信使 RNA (mRNA) 中含有滑动序列。我们的发现解释了为什么二苯胺在进化上是保守的，以及为什么它在动物发育中至关重要。我们的结果还表明，通过二苯胺调节滑序列的翻译可能是一种广泛使用的调节真核生物翻译的机制，这与重新编码假设不同。 Diphthamide 是一种仅在翻译延伸因子 2 (EF2) 上发现的修饰，被提议用于抑制翻译中的 -1 移码。尽管二邻苯二甲酰胺在所有真核生物中都是保守的，但细胞中哪些蛋白质受到二邻苯二甲酰胺缺失的影响尚不清楚。通过对潜在的-1移码位点进行全基因组分析，我们发现雷帕霉素复合物1（TORC1）/哺乳动物TORC1（mTORC1）信号通路的靶标受到二苯胺删除的影响。酵母中二苯胺的缺乏会抑制 TORC1 激活蛋白 Vam6 和 Rtc1 的翻译。有趣的是，TORC1信号传导还促进二苯甲酰胺生物合成，这表明二苯甲酰胺形成正反馈环以促进营养丰富的条件下的翻译。我们的结果解释了为什么二苯乙醇胺在进化上是保守的，以及为什么二苯乙醇胺缺失会导致严重的发育缺陷。
Diphthamide is a posttranslational modification that has been known since the 1970s. It is conserved in all eukaryotic cells, and its biosynthesis requires at least seven proteins. However, its exact biological function has remained unclear. Our results demonstrate that diphthamide promotes target of rapamycin (TOR) signaling by promoting the translation of two proteins in the target of rapamycin complex 1 (TORC1) pathway that contain slippery sequences in their messenger RNA (mRNA). Our finding explained why diphthamide is evolutionarily conserved and why it is crucial in animal development. Our results also suggest that regulating the translation of slippery sequences by diphthamide could be a widely used mechanism to tune translation in eukaryotes, which is different from the recoding hypothesis. Diphthamide, a modification found only on translation elongation factor 2 (EF2), was proposed to suppress −1 frameshifting in translation. Although diphthamide is conserved among all eukaryotes, exactly what proteins are affected by diphthamide deletion is not clear in cells. Through genome-wide profiling for a potential −1 frameshifting site, we identified that the target of rapamycin complex 1 (TORC1)/mammalian TORC1 (mTORC1) signaling pathway is affected by deletion of diphthamide. Diphthamide deficiency in yeast suppresses the translation of TORC1-activating proteins Vam6 and Rtc1. Interestingly, TORC1 signaling also promotes diphthamide biosynthesis, suggesting that diphthamide forms a positive feedback loop to promote translation under nutrient-rich conditions. Our results provide an explanation for why diphthamide is evolutionarily conserved and why diphthamide deletion can cause severe developmental defects.
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