Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Biological Chemistry Pub Date : 2024-10-19 DOI:10.1016/j.jbc.2024.107909
Sumire Ishida-Ishihara, Kan Yaguchi, Sena Miura, Ryoto Nomura, QiJiao Wang, Koya Yoshizawa, Kimino Sato, Guang Yang, Krisztina Veszelyi, Gabor Banhegyi, Eva Margittai, Ryota Uehara
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Abstract

Mammalian somatic cells are generally unstable in the haploid state, resulting in haploid-to-diploid conversion within a short time frame. However, cellular and molecular principles that limit the sustainability of somatic haploidy remain unknown. In this study, we found the haploidy-linked vulnerability to endoplasmic reticulum (ER) stress as a critical cause of haploid intolerance in human somatic cells. Pharmacological induction of ER stress selectively induced apoptosis in haploid cells, facilitating the replacement of haploids by coexisting diploidized cells in a caspase-dependent manner. Biochemical analyses revealed that unfolded protein response (UPR) was activated with similar dynamics between haploids and diploids upon ER stress induction. However, haploids were less efficient in solving proteotoxic stress, resulting in a bias toward a proapoptotic mode of UPR signaling. Artificial replenishment of chaperone function substantially alleviated the haploidy-linked upregulation of proapoptotic signaling and improved haploid cell retention under tunicamycin-induced ER stress. These data demonstrate that the ER stress-driven haploid instability stems from inefficient proteostatic control that alters the functionality of UPR to cause apoptosis selectively in haploids. Interestingly, haploids suffered a higher level of protein aggregation even in unperturbed conditions, and the long-term stability of the haploid state was significantly improved by alleviating their natural proteotoxicity. Based on these results, we propose that the haploidy-specific vulnerability to ER stress creates a fundamental cause of haploid intolerance in mammalian somatic cells. Our findings provide new insight into the principle that places a stringent restriction on the evolution of animal life cycles.

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人类体细胞单倍体不稳定性的根源在于ER平衡调节的脆弱性。
哺乳动物体细胞的单倍体状态通常不稳定,会在短时间内从单倍体转变为二倍体。然而,限制体细胞单倍体持续性的细胞和分子原理仍然未知。在这项研究中,我们发现与单倍体相关的对ER应激的脆弱性是人类体细胞单倍体不耐受的关键原因。药理诱导ER应激可选择性地诱导单倍体细胞凋亡,以一种依赖于Caspase的方式促进单倍体细胞被同时存在的二倍体细胞取代。生化分析表明,在ER应激诱导下,单倍体和二倍体以相似的动态激活了未折叠蛋白反应(UPR)。然而,单倍体在解决蛋白毒性应激方面效率较低,导致 UPR 信号偏向于促凋亡模式。人工补充伴侣蛋白功能大大缓解了单倍体与促凋亡信号的上调有关,并改善了单倍体细胞在曲安奈德霉素诱导的ER应激下的存活率。这些数据表明,ER应激驱动的单倍体不稳定性源于蛋白静态控制的低效,它改变了UPR的功能,从而选择性地导致单倍体细胞凋亡。有趣的是,即使在未受干扰的条件下,单倍体也会遭受更高水平的蛋白质聚集,而通过减轻其天然的蛋白质毒性,单倍体状态的长期稳定性得到了显著改善。基于这些结果,我们认为单倍体对ER应激的特异脆弱性是哺乳动物体细胞单倍体不耐受的根本原因。我们的研究结果使我们对严格限制动物生命周期进化的原理有了新的认识。
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Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
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4.20%
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期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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