自噬调控核糖体生物发生及其机制研究

自噬是真核生物高度保守的溶酶体依赖的降解途径，对于细胞内环境稳态的维持非常重要。自噬缺陷与肿瘤的发生发展密切相关，然而自噬如何调控肿瘤的发生发展仍然知之甚少。快速增殖的肿瘤细胞需要合成更多的蛋白。最近我们发现，自噬缺陷会激活核糖体RNA的转录，促进核糖体的生物发生，进而促进蛋白合成以及肿瘤细胞的生长与增殖。但是，在自噬缺陷的细胞中敲低自噬性底物p62，则不会激活核糖体RNA的转录，表明p62的累积是自噬缺陷激活核糖体RNA转录的主要原因。并且，我们发现自噬缺陷累积的p62在核仁处有明显分布，而核仁是核糖体RNA转录的主要场所，提示p62可能直接参与核糖体RNA的转录。本项目将深入探究自噬及其底物p62在核糖体生物发生中的作用，通过细胞、生化和遗传学等研究手段，阐明核仁定位的p62促进核糖体RNA转录的分子机制，明确其对于蛋白合成和细胞增殖的影响，为自噬调控肿瘤的发生发展提供新的分子机制。

Autophagy is an evolutionarily conserved lysosome-dependent degradation pathway in eukaryotic cells, which delivers protein aggregates and damaged organelles to lysosome for degradation and helps maintain cellular homeostasis. Autophagy deficiency drives multiple tumors development in animal models. However, the underlying mechanism of autophagy in tumorigenesis remains largely unknown. Rapidly proliferating cancer cells need to synthesize more macromolecules such as proteins and nucleic acids. In our preliminary work, we found that autophagy deficiency leads to activation of ribosomal RNA transcription and promotion of ribosome biogenesis, which facilitates protein synthesis and drives cell proliferation. Furthermore, the accumulating p62 by autophagy deficiency partially localizes to the nucleolus, the main site for ribosomal RNA transcription, indicating that nucleolar p62 may directly participates in ribosomal RNA synthesis. This study would explore the function and molecular mechanism of atuophagy and autophagic substrate p62 in ribosome biogenesis, protein synthesis and cell proliferation. Our study would uncover the role of autopahgy in ribosome biogenesis and provide a novel molecular link between autophagy and tumorigenesis.