Bartolutti Constantine, Kim Allison J, Brar Gloria A
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720, USA.
California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, 94720, USA.
bioRxiv. 2024 Nov 24:2024.11.22.624941. doi: 10.1101/2024.11.22.624941.
The Unfolded Protein Response (UPR) was discovered in budding yeast as a mechanism that allows cells to adapt to ER stress. While the Ire1 branch of this pathway is highly conserved, it is not thought to be important for cellular homeostasis in the absence of stress. Surprisingly, we found that removal of UPR activity led to pervasive aneuploidy in budding yeast cells, suggesting selective pressure resulting from UPR-deficiency. Aneuploid UPR-deficient cells grew better than euploid cells, but exhibited heightened general proteostatic stress, a hallmark of aneuploidy in wild-type cells. Modulation of key genes involved in ER proteostasis that were encoded on aneuploid chromosomes, could phenocopy the effects of aneuploidy, indicating that the reason cells require UPR activity to maintain euploidy is to counteract protein folding stress in the ER. In support of this model, aneuploidy in UPR-deficient cells can be prevented by expression of a UPR-independent general ER chaperone. Overall, our results indicate an unexpected role for the UPR in basal cell growth that is sufficiently important for cells to accept the costly trade-off of aneuploidy in the absence of UPR activity.
未折叠蛋白反应（UPR）最初是在芽殖酵母中被发现的，它是一种使细胞能够适应内质网应激的机制。虽然该信号通路中的Ire1分支高度保守，但在无应激状态下，人们认为它对细胞内稳态并不重要。令人惊讶的是，我们发现去除UPR活性会导致芽殖酵母细胞中普遍出现非整倍体现象，这表明UPR缺陷会产生选择性压力。非整倍体的UPR缺陷细胞比整倍体细胞生长得更好，但表现出更高的整体蛋白质稳态应激，这是野生型细胞中非整倍体的一个标志。对非整倍体染色体上编码的内质网蛋白质稳态相关关键基因进行调控，可模拟非整倍体的效应，这表明细胞需要UPR活性来维持整倍体的原因是为了抵消内质网中的蛋白质折叠应激。支持这一模型的是，通过表达一种不依赖UPR的通用内质网伴侣蛋白，可以防止UPR缺陷细胞中出现非整倍体现象。总体而言，我们的研究结果表明，UPR在基础细胞生长中具有意想不到的作用，这一作用对细胞来说非常重要，以至于在缺乏UPR活性的情况下，细胞会接受非整倍体这种代价高昂的权衡。
