Yorkie drives supercompetition by non-autonomous induction of autophagy via bantam microRNA in Drosophila
Yorkie drives supercompetition by non-autonomous induction of autophagy via bantam microRNA in Drosophila
复制标题
Yorkie 通过在果蝇中通过 bantam microRNA 非自主诱导自噬来驱动超级竞争
DOI：
10.1016/j.cub.2022.01.016
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发表时间：
2022
期刊：
影响因子：
9.2
通讯作者：
Igaki Tatsushi
中科院分区：
文献类型：
--
作者：
Nagata Rina;Akai Nanami;Kondo Shu;Saito Kuniaki;Ohsawa Shizue;Igaki Tatsushi
肿瘤抑制因子Hippo通路中的突变导致转录共激活因子Yorkie（Yki）的激活，其自主增强细胞增殖并非自主地引起细胞死亡。虽然Yki诱导的细胞增殖已被广泛研究，但Yki导致附近野生型细胞死亡的机制（一种称为超竞争的现象）及其在肿瘤发生中的作用仍然未知。在这里，我们表明，Yki诱导的超竞争是必不可少的肿瘤发生，是由非自主诱导的自噬。Hippo途径突变的细胞克隆激活Yki并导致果蝇眼触角盘中自主肿瘤发生和非自主细胞死亡。通过对果蝇的基因筛选，我们发现自噬相关基因或周围野生型细胞中NF-κB基因的突变阻断了脂肪诱导的肿瘤发生和超竞争。从机制上讲，脂肪突变细胞上调Yki靶向microRNAbantam，其通过激活TOR信号传导提高蛋白质合成水平。这诱导邻近野生型细胞中自噬的升高，这导致IκB Cactus的下调，从而引起NF-κ B介导的细胞死亡基因的诱导。至关重要的是，bantam的上调足以使细胞成为超级竞争者，而内源性bantam的下调足以使细胞成为细胞竞争的失败者。我们的数据表明，具有升高的Yki-bantam信号传导的细胞通过非自主诱导杀死邻近野生型细胞的自噬而引起肿瘤发生。
Mutations in the tumor-suppressor Hippo pathway lead to activation of the transcriptional coactivator Yorkie (Yki), which enhances cell proliferation autonomously and causes cell death non-autonomously. While Yki-induced cell proliferation has extensively been studied, the mechanism by which Yki causes cell death in nearby wild-type cells, a phenomenon called supercompetition, and its role in tumorigenesis remained unknown. Here, we show that Yki-induced supercompetition is essential for tumorigenesis and is driven by non-autonomous induction of autophagy. Clones of cells mutant for a Hippo pathway componentfatactivate Yki and cause autonomous tumorigenesis and non-autonomous cell death inDrosophilaeye-antennal discs. Through a genetic screen inDrosophila, we find that mutations in autophagy-related genes or NF-κB genes in surrounding wild-type cells block bothfat-induced tumorigenesis and supercompetition. Mechanistically,fatmutant cells upregulate Yki-target microRNAbantam, which elevates protein synthesis levels via activation of TOR signaling. This induces elevation of autophagy in neighboring wild-type cells, which leads to downregulation of IκB Cactus and thus causes NF-κB-mediated induction of the cell death genehid. Crucially, upregulation ofbantamis sufficient to make cells to be supercompetitors and downregulation of endogenousbantamis sufficient for cells to become losers of cell competition. Our data indicate that cells with elevated Yki-bantamsignaling cause tumorigenesis by non-autonomous induction of autophagy that kills neighboring wild-type cells.