Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness
Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness
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DOI：
10.7554/elife.43002
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发表时间：
2019-03
期刊：
影响因子：
7.7
通讯作者：
Blake W Tye;Nicoletta Commins;Lillia V. Ryazanova;M. Wühr;Michael Springer;David Pincus;David Pincus-David-Pincu
中科院分区：
文献类型：
--
作者：
Blake W Tye;Nicoletta Commins;Lillia V. Ryazanova;M. Wühr;Michael Springer;David Pincus;David Pincus-David-Pincu
为了实现最大限度的生长，细胞必须管理大量的核糖体蛋白（r蛋白）和RNA（rRNA），以每分钟产生数千个核糖体。尽管核糖体在所有细胞中都是必不可少的，但核糖体生物合成的自然中断导致异质性表型。在这里，我们模拟这些扰动在酿酒酵母，并表明，核糖体生物合成的挑战，导致蛋白质稳态的急性损失。R-蛋白和rRNA合成的不平衡导致新合成的孤儿R-蛋白的快速聚集，并损害必要的细胞过程，细胞通过激活蛋白质稳态基因来缓解。外源性支持蛋白质稳态网络增加了细胞适应性，面对核糖体组装的挑战，证明了孤儿r蛋白对细胞表型的直接贡献。我们建议，核糖体组装是一个关键的脆弱性，蛋白质稳态维护增殖细胞，可能会受到不同的遗传，环境和外源性干扰，产生孤儿r-蛋白。
To achieve maximal growth, cells must manage a massive economy of ribosomal proteins (r-proteins) and RNAs (rRNAs) to produce thousands of ribosomes every minute. Although ribosomes are essential in all cells, natural disruptions to ribosome biogenesis lead to heterogeneous phenotypes. Here, we model these perturbations in Saccharomyces cerevisiae and show that challenges to ribosome biogenesis result in acute loss of proteostasis. Imbalances in the synthesis of r-proteins and rRNAs lead to the rapid aggregation of newly synthesized orphan r-proteins and compromise essential cellular processes, which cells alleviate by activating proteostasis genes. Exogenously bolstering the proteostasis network increases cellular fitness in the face of challenges to ribosome assembly, demonstrating the direct contribution of orphan r-proteins to cellular phenotypes. We propose that ribosome assembly is a key vulnerability of proteostasis maintenance in proliferating cells that may be compromised by diverse genetic, environmental, and xenobiotic perturbations that generate orphan r-proteins.