Non-degradable autophagic vacuoles are indispensable for cell competition
Non-degradable autophagic vacuoles are indispensable for cell competition
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DOI：
10.1016/j.celrep.2022.111292
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发表时间：
2022-08-30
期刊：
影响因子：
8.8
通讯作者：
Kon, Shunsuke
中科院分区：
文献类型：
--
作者：
Akter, Eilma;Tasaki, Yukihiro;Kon, Shunsuke
细胞竞争是从组织中清除不需要的细胞的过程。根尖挤出是正常上皮细胞移除转化细胞的一种方式，但目前尚不清楚这一过程是如何机械影响的。在这项研究中，我们表明，由于溶酶体功能障碍，在被正常细胞包围的RasV12转化细胞中，自噬和内吞通量减弱，并且对溶酶体活性的化学操纵损害了顶端挤出。我们进一步发现，缺乏自噬启动机制的RasV12细胞对正常细胞施加的消除压力具有抵抗力，这表明细胞竞争需要不可降解的自噬空泡。此外，体内分析显示，自噬消融的RasV12细胞不太容易被细胞竞争消除，剩余的转化细胞破坏导管的完整性，导致慢性胰腺炎。总而言之，我们的发现阐明了自噬在细胞竞争中的积极作用，并揭示了自噬在转化细胞出现时保持动态平衡的功能。
Cell competition is a process by which unwanted cells are eliminated from tissues. Apical extrusion is one mode whereby normal epithelial cells remove transformed cells, but it remains unclear how this process is mechanically effected. In this study, we show that autophagic and endocytic fluxes are attenuated in RasV12-transformed cells surrounded by normal cells due to lysosomal dysfunction, and that chemical manipulation of lysosomal activity compromises apical extrusion. We further find that RasV12 cells deficient in autophagy initiation machinery are resistant to elimination pressure exerted by normal cells, suggesting that non-degradable autophagic vacuoles are required for cell competition. Moreover, in vivo analysis revealed that autophagy-ablated RasV12 cells are less readily eliminated by cell competition, and remaining transformed cells destroy ductal integrity, leading to chronic pancreatitis. Collectively, our findings illuminate a positive role for autophagy in cell competition and reveal a homeostasis-preserving function of autophagy upon emergence of transformed cells.