A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies.
A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies.
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DOI：
10.1016/j.devcel.2021.06.013
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发表时间：
2021-07-26
影响因子：
11.8
通讯作者：
Barna M
中科院分区：
文献类型：
--
作者：
Tiu GC;Kerr CH;Forester CM;Krishnarao PS;Rosenblatt HD;Raj N;Lantz TC;Zhulyn O;Bowen ME;Shokat L;Attardi LD;Ruggero D;Barna M
在核糖体病中，核糖体组分的干扰表达导致组织特异性表型。核糖体是一种无处不在的细胞机器，是什么原因导致了这种组织选择性的表现，这仍然是一个谜。结合小鼠遗传学和体内核糖体分析，我们观察肢体图案表型在核糖体蛋白（RP）单倍不足的胚胎和发现控制肢体发育的转录本的选择性翻译变化。令人惊讶的是，这两个损失的p53，这是由RP单倍不足激活，并增强蛋白质合成拯救这些表型。这些发现的解释，鉴定p53作为一个主调节蛋白质合成，至少部分，通过转录激活4 E-BP 1。4 E-BP 1，一个关键的翻译调节因子，反过来，促进p53下游翻译组的选择性变化，从而解释了RP单倍不足如何引起基因表达的特异性。这些结果提供了一个综合模型，以了解如何在体内组织特异性表型出现在核糖体病。Tiu等人表明，发育中的哺乳动物肢体中的核糖体蛋白（RP）单倍不足导致图案化缺陷，这部分是由p53介导的翻译调节通过诱导4 E-BP 1（一种翻译阻遏物）驱动的。这一发现将p53和翻译失调整合到RP单倍不足的体内模型中。
In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes. What accounts for such tissue-selective manifestations as a result of mutations in the ribosome, a ubiquitous cellular machine, has remained a mystery. Combining mouse genetics and in vivo ribosome profiling, we observe limb patterning phenotypes in ribosomal protein (RP) haploinsufficient embryos and uncover selective translational changes of transcripts controlling limb development. Surprisingly, both loss of p53, which is activated by RP haploinsufficiency, and augmented protein synthesis rescue these phenotypes. These findings are explained by the identification that p53 functions as a master regulator of protein synthesis, at least in part, through transcriptional activation of 4E-BP1. 4E-BP1, a key translational regulator, in turn, facilitates selective changes in the translatome downstream of p53, and thereby explains how RP haploinsufficiency may elicit specificity to gene expression. These results provide an integrative model to understand how in vivo tissue-specific phenotypes emerge in ribosomopathies. Tiu et al. show that ribosomal protein (RP) haploinsufficiency in the developing mammalian limb leads to patterning defects driven in part by p53-mediated translational regulation through induction of 4E-BP1, a translational repressor. This finding integrates p53 and translational dysregulation into a cohesive in vivo model of RP haploinsufficiency.
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