当前位置: X-MOL 学术BMC Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Aneuploidy-induced proteotoxic stress can be effectively tolerated without dosage compensation, genetic mutations, or stress responses.
BMC Biology ( IF 4.4 ) Pub Date : 2020-09-08 , DOI: 10.1186/s12915-020-00852-x
Katherine E Larrimore 1, 2 , Natalia S Barattin-Voynova 1 , David W Reid 3, 4 , Davis T W Ng 1, 3, 5
Affiliation  

The protein homeostasis (proteostasis) network maintains balanced protein synthesis, folding, transport, and degradation within a cell. Failure to maintain proteostasis is associated with aging and disease, leading to concerted efforts to study how the network responds to various proteotoxic stresses. This is often accomplished using ectopic overexpression of well-characterized, model misfolded protein substrates. However, how cells tolerate large-scale, diverse burden to the proteostasis network is not understood. Aneuploidy, the state of imbalanced chromosome content, adversely affects the proteostasis network by dysregulating the expression of hundreds of proteins simultaneously. Using aneuploid haploid yeast cells as a model, we address whether cells can tolerate large-scale, diverse challenges to the proteostasis network. Here we characterize several aneuploid Saccharomyces cerevisiae strains isolated from a collection of stable, randomly generated yeast aneuploid cells. These strains exhibit robust growth and resistance to multiple drugs which induce various forms of proteotoxic stress. Whole genome re-sequencing of the strains revealed this was not the result of genetic mutations, and transcriptome profiling combined with ribosome footprinting showed that genes are expressed and translated in accordance to chromosome copy number. In some strains, various facets of the proteostasis network are mildly upregulated without chronic activation of environmental stress response or heat shock response pathways. No severe defects were observed in the degradation of misfolded proteins, using model misfolded substrates of endoplasmic reticulum-associated degradation or cytosolic quality control pathways, and protein biosynthesis capacity was not impaired. We show that yeast strains of some karyotypes in the genetic background studied here can tolerate the large aneuploidy-associated burden to the proteostasis machinery without genetic changes, dosage compensation, or activation of canonical stress response pathways. We suggest that proteotoxic stress, while common, is not always an obligate consequence of aneuploidy, but rather certain karyotypes and genetic backgrounds may be able to tolerate the excess protein burden placed on the protein homeostasis machinery. This may help clarify how cancer cells are paradoxically both highly aneuploid and highly proliferative at the same time.

中文翻译:


非整倍体诱导的蛋白毒性应激可以有效耐受,无需剂量补偿、基因突变或应激反应。



蛋白质稳态(蛋白质稳态)网络维持细胞内蛋白质合成、折叠、运输和降解的平衡。无法维持蛋白质稳态与衰老和疾病有关,因此需要共同努力研究网络如何应对各种蛋白质毒性应激。这通常是通过使用特征明确的模型错误折叠蛋白质底物的异位过度表达来实现的。然而,细胞如何承受蛋白质稳态网络的大规模、多样化的负担尚不清楚。非整倍性是染色体含量不平衡的状态,它会同时失调数百种蛋白质的表达,从而对蛋白质稳态网络产生不利影响。使用非整倍体单倍体酵母细胞作为模型,我们解决了细胞是否能够耐受蛋白质稳态网络的大规模、多样化的挑战。在这里,我们表征了从稳定的、随机生成的酵母非整倍体细胞集合中分离出的几种非整倍体酿酒酵母菌株。这些菌株表现出强劲的生长和对诱导各种形式的蛋白毒性应激的多种药物的抗性。对菌株的全基因组重新测序表明这不是基因突变的结果,转录组分析与核糖体足迹相结合表明基因根据染色体拷贝数表达和翻译。在某些菌株中,蛋白质稳态网络的各个方面都轻度上调,而没有环境应激反应或热休克反应途径的慢性激活。使用内质网相关降解或胞质质量控制途径的模型错误折叠底物,在错误折叠蛋白质的降解中没有观察到严重缺陷,并且蛋白质生物合成能力没有受损。 我们表明,在此研究的遗传背景中,某些核型的酵母菌株可以耐受蛋白质稳态机制的大量非整倍性相关负担,而无需遗传改变、剂量补偿或经典应激反应途径的激活。我们认为,蛋白质毒性应激虽然常见,但并不总是非整倍性的必然结果,而是某些核型和遗传背景可能能够耐受蛋白质稳态机制上的过量蛋白质负担。这可能有助于阐明癌细胞如何矛盾地同时具有高度非整倍体和高度增殖性。
更新日期:2020-09-08
down
wechat
bug