Aneuploidy-induced cellular stresses limit autophagic degradation.
Aneuploidy-induced cellular stresses limit autophagic degradation.
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DOI：
10.1101/gad.269118.115
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发表时间：
2015-10-01
影响因子：
10.5
通讯作者：
Amon A
中科院分区：
文献类型：
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作者：
Santaguida S;Vasile E;White E;Amon A
桑塔吉达等人。发现非整倍体细胞激活转录因子 TFEB（自噬和溶酶体基因表达的主要调节因子），从而增加自噬介导的蛋白质降解所需基因的表达。不平衡的核型，一种称为非整倍性的情况，对细胞生理学具有深远的影响，是癌症的一个标志。非整倍体细胞经历许多由非整倍体诱导的蛋白质组变化引起的应激。非整倍体相关的应激如何影响细胞以及细胞是否对其做出反应才刚刚开始被了解。在这里，我们展示了自噬体货物（例如蛋白质聚集体）在非整倍体细胞的溶酶体内积累。这会引起溶酶体应激反应。非整倍体细胞激活转录因子 TFEB（自噬和溶酶体基因表达的主要调节因子），从而增加自噬介导的蛋白质降解所需基因的表达。在蛋白酶体功能受到抑制的细胞中也观察到溶酶体内自噬物质的积累和 TFEB 反应基因的激活，表明蛋白毒性应激导致 TFEB 激活。我们的结果揭示了 TFEB 介导的溶酶体应激反应是非整倍体状态的普遍特征。
Santaguida et al. find that aneuploid cells activate the transcription factor TFEB, a master regulator of autophagic and lysosomal gene expression, thereby increasing the expression of genes needed for autophagy-mediated protein degradation. An unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Aneuploid cells experience a number of stresses that are caused by aneuploidy-induced proteomic changes. How the aneuploidy-associated stresses affect cells and whether cells respond to them are only beginning to be understood. Here we show that autophagosomal cargo such as protein aggregates accumulate within lysosomes in aneuploid cells. This causes a lysosomal stress response. Aneuploid cells activate the transcription factor TFEB, a master regulator of autophagic and lysosomal gene expression, thereby increasing the expression of genes needed for autophagy-mediated protein degradation. Accumulation of autophagic cargo within the lysosome and activation of TFEB-responsive genes are also observed in cells in which proteasome function is inhibited, suggesting that proteotoxic stress causes TFEB activation. Our results reveal a TFEB-mediated lysosomal stress response as a universal feature of the aneuploid state.