Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis, and genomic stability.
Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis, and genomic stability.
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DOI：
10.1158/0008-5472.can-12-4142
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发表时间：
2013-07-15
期刊：
影响因子：
11.2
通讯作者：
Mograbi B
中科院分区：
文献类型：
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作者：
Belaid A;Cerezo M;Chargui A;Corcelle-Termeau E;Pedeutour F;Giuliano S;Ilie M;Rubera I;Tauc M;Barale S;Bertolotto C;Brest P;Vouret-Craviari V;Klionsky DJ;Carle GF;Hofman P;Mograbi B
信号蛋白的降解是细胞可以控制其自身生长的最强大的肿瘤抑制机制之一。在这里，我们确定RHOA作为自噬维持基因组稳定性的分子靶点。具体地，通过v-ATP酶a3（TCIRG 1）亚基的损失抑制自噬体降解足以诱导非整倍性。在这种表型的基础上，活性RHOA通过p62（SQSTM 1）被隔离在自体溶酶体内，并且不能定位于质膜或纺锤体中间体。相反，ATG 5 shRNA对自噬体形成的抑制显著增加了活性RHOA在中间体的定位，然后扩散到侧翼区。因此，我们研究的所有损害自噬的方法（无论缺陷：自噬体形成，隔离或降解）都会驱动胞质分裂失败，多核化和非整倍性，这些过程直接影响癌症进展。因此，我们报道了自噬缺陷与人肺癌中RHOA的高表达之间的正相关性。因此，我们提出，自噬可能部分作为一种保护机制，降解，从而保持适当水平的活性RHOA在中体忠实完成胞质分裂和基因组遗传。
Degradation of signaling proteins is one of the most powerful tumor suppressive mechanisms by which a cell can control its own growth. Here, we identify RHOA as the molecular target by which autophagy maintains genomic stability. Specifically, inhibition of autophagosome degradation by the loss of the v-ATPase a3 (TCIRG1) subunit is sufficient to induce aneuploidy. Underlying this phenotype, active RHOA is sequestered via p62 (SQSTM1) within autolysosomes, and fails to localize to the plasma membrane or to the spindle midbody. Conversely, inhibition of autophagosome formation by ATG5 shRNA dramatically increases localization of active RHOA at the midbody, followed by diffusion to the flanking zones. As a result, all of the approaches we examined that compromise autophagy (irrespective of the defect: autophagosome formation, sequestration or degradation) drive cytokinesis failure, multinucleation, and aneuploidy, processes that directly have an impact upon cancer progression. Consistently, we report a positive correlation between autophagy defects and the higher expression of RHOA in human lung carcinoma. We therefore propose that autophagy may act in part as a safeguard mechanism that degrades and thereby maintains the appropriate level of active RHOA at the midbody for faithful completion of cytokinesis and genome inheritance.