生物
半胱氨酸蛋白酶
细胞凋亡
应力颗粒
细胞生物学
串扰
内源性凋亡
程序性细胞死亡
癌细胞
生物化学
癌症
遗传学
基因
翻译(生物学)
物理
光学
信使核糖核酸
作者
Daichi Fujikawa,Takanori Nakamura,Daisuke Yoshioka,Zizheng Li,Hisashi Moriizumi,Mari Taguchi,Noriko Tokai‐Nishizumi,Hiroko Kozuka‐Hata,Masaaki Oyama,Mutsuhiro Takekawa
出处
期刊:Current Biology
[Elsevier]
日期:2023-05-01
卷期号:33 (10): 1967-1981.e8
被引量:10
标识
DOI:10.1016/j.cub.2023.04.012
摘要
Cytoplasmic stress granules (SGs) are phase-separated membrane-less organelles that form in response to various stress stimuli. SGs are mainly composed of non-canonical stalled 48S preinitiation complexes. In addition, many other proteins also accumulate into SGs, but the list is still incomplete. SG assembly suppresses apoptosis and promotes cell survival under stress. Furthermore, hyperformation of SGs is frequently observed in various human cancers and accelerates tumor development and progression by reducing stress-induced damage of cancer cells. Therefore, they are of clinical importance. However, the precise mechanism underlying SG-mediated inhibition of apoptosis remains ill-defined. Here, using a proximity-labeling proteomic approach, we comprehensively analyzed SG-resident proteins and identified the executioner caspases, caspase-3 and -7, as SG components. We demonstrate that accumulation of caspase-3/7 into SGs is mediated by evolutionarily conserved amino acid residues within their large catalytic domains and inhibits caspase activities and consequent apoptosis induced by various stresses. Expression of an SG-localization-deficient caspase-3 mutant in cells largely counteracted the anti-apoptotic effect of SGs, whereas enforced relocalization of the caspase-3 mutant to SGs restored it. Thus, SG-mediated sequestration of executioner caspases is a mechanism underlying the broad cytoprotective function of SGs. Furthermore, using a mouse xenograft tumor model, we show that this mechanism prevents cancer cells from apoptosis in tumor tissues, thereby promoting cancer progression. Our results reveal the functional crosstalk between SG-mediated cell survival and caspase-mediated cell death signaling pathways and delineate a molecular mechanism that dictates cell-fate decisions under stress and promotes tumorigenesis.
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