Autophagy deficiency activates rDNA transcription
Autophagy deficiency activates rDNA transcription
复制标题
DOI：
10.1080/15548627.2021.1974178
复制
发表时间：
2021-10-04
期刊：
影响因子：
13.3
通讯作者：
Wan, Wei
中科院分区：
文献类型：
--
作者：
Xu, Yinfeng;Wu, Yaosen;Wan, Wei
自噬是一种高度保守的溶酶体依赖性降解途径，通过降解细胞内组分来调节细胞代谢。在这项研究中，我们通过揭示自噬在核糖体RNA（rRNA）合成中的调节作用，将自噬与RNA代谢联系起来。自噬缺陷细胞表现出更高的47 S前体rRNA水平，这是由SQSTM 1/p62（隔离体1）而不是其他自噬受体的积累引起的。从机制上讲，SQSTM 1的积累增强了MTOR（雷帕霉素激酶的机械靶点）复合物1（MTORC 1）信号传导的激活，并促进了RNA聚合酶I前起始复合物在核糖体DNA（rDNA）启动子处的组装，这导致从rDNA转录的47 S rRNA增加。在功能上，自噬缺陷促进蛋白质合成，细胞生长和细胞增殖，这两者都依赖于SQSTM 1的积累。总之，我们的研究结果表明，自噬缺陷通过激活rDNA转录参与RNA代谢，并为自噬相关疾病（包括多种类型的癌症）中的细胞代谢重编程提供了新的机制。
Macroautophagy/autophagy, a highly conserved lysosome-dependent degradation pathway, has been intensively studied in regulating cell metabolism by degradation of intracellular components. In this study, we link autophagy to RNA metabolism by uncovering a regulatory role of autophagy in ribosomal RNA (rRNA) synthesis. Autophagy-deficient cells exhibit much higher 47S precursor rRNA level, which is caused by the accumulation of SQSTM1/p62 (sequestosome 1) but not other autophagy receptors. Mechanistically, SQSTM1 accumulation potentiates the activation of MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) signaling and promotes the assembly of RNA polymerase I pre-initiation complex at ribosomal DNA (rDNA) promoters, which leads to an increase of 47S rRNA transcribed from rDNA. Functionally, autophagy deficiency promotes protein synthesis, cell growth and cell proliferation, both of which are dependent on SQSTM1 accumulation. Taken together, our findings suggest that autophagy deficiency is involved in RNA metabolism by activating rDNA transcription and provide novel mechanisms for the reprogramming of cell metabolism in autophagy-related diseases including multiple types of cancers.