Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts
Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts
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DOI：
10.1101/2021.03.26.437120
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发表时间：
2022-06
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通讯作者：
Kojiro Suda;Y. Moriyama;Yumiko Masukagami;N. Razali;Yatzu Chiu;K. Nishimura;Hunter Barbee;H. Takase;Shinju Sugiyama;Yoshikatsu Sato;T. Higashiyama;Yoshikazu Johmura;M. Nakanishi;Keiko Kono
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作者：
Kojiro Suda;Y. Moriyama;Yumiko Masukagami;N. Razali;Yatzu Chiu;K. Nishimura;Hunter Barbee;H. Takase;Shinju Sugiyama;Yoshikatsu Sato;T. Higashiyama;Yoshikazu Johmura;M. Nakanishi;Keiko Kono
由于环境干扰和细胞自主活动，质膜损伤（PMD）发生在所有细胞类型中。然而，除了恢复或死亡之外，PMD的细胞结局在很大程度上仍然未知。在这里，使用芽殖酵母和正常的人类成纤维细胞，我们表明，细胞衰老，不可逆的细胞周期停滞，有助于有机体老化，是PMD的长期结果。为了确定PMD反应所必需的基因，我们开发了一种简单的PMD损伤检测方法，使用去污剂，并进行了系统的酵母全基因组筛选。筛选出48个基因。筛选中的最高命中是转运所需的内体分选复合物（ESCRT）基因，其编码真核生物中充分描述的质膜修复蛋白。出乎意料的是，复制寿命调节基因在我们的48个命中中富集。这一发现表明PMD反应和复制寿命调节之间存在密切的遗传关联。事实上，我们发现PMD限制了芽殖酵母的复制寿命，ESCRT激活剂AAA-ATPase VPS 4-过表达延长了它。此外，在正常人成纤维细胞中，我们发现PMD通过Ca 2 +-p53轴而不是主要的衰老途径ATM/ATR途径诱导过早衰老。与酵母中的结果一致，ESCRT-III，CHMP 4 B的瞬时过表达抑制了正常人成纤维细胞中PMD依赖性衰老。我们的研究提出PMD限制了两种不同真核细胞类型的细胞寿命，并突出了一种未被充分认识但普遍存在的衰老细胞亚型，即PMD依赖性衰老细胞。
Plasma membrane damage (PMD) occurs in all cell types due to environmental perturbation and cell-autonomous activities. However, cellular outcomes of PMD remain largely unknown except for recovery or death. Here, using budding yeast and normal human fibroblasts, we show that cellular senescence, irreversible cell cycle arrest contributing to organismal aging, is the long-term outcome of PMD. To identify the genes essential for PMD response, we developed a simple PMD-damaging assay using a detergent and performed a systematic yeast genome-wide screen. The screen identified 48 genes. The top hits in the screen are the endosomal sorting complexes required for transport (ESCRT) genes, encoding the well-described plasma membrane repair proteins in eukaryotes. Unexpectedly, the replicative lifespan regulator genes are enriched in our 48 hits. This finding suggests a close genetic association between the PMD response and the replicative lifespan regulations. Indeed, we show that PMD limits the replicative lifespan in budding yeast; the ESCRT activator AAA-ATPase VPS4-overexpression extends it. These results suggest that PMD limits replicative lifespan in budding yeast. Moreover, in normal human fibroblasts, we find that PMD induces premature senescence via the Ca2+-p53 axis but not the major senescence pathway, ATM/ATR pathway. Consistent with the results in yeast, transient overexpression of ESCRT-III, CHMP4B, suppressed the PMD-dependent senescence in normal human fibroblasts. Our study proposes that PMD limits cellular lifespan in two different eukaryotic cell types and highlights an underappreciated but ubiquitous senescent cell subtype, namely PMD-dependent senescent cells.