Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
Department of Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands.
Cell Rep. 2019 Sep 24;28(13):3486-3496.e6. doi: 10.1016/j.celrep.2019.08.069.
The target of rapamycin complex 1 (TORC1) is a master regulator of cell homeostasis, which promotes anabolic reactions and synchronously inhibits catabolic processes such as autophagy-mediated protein degradation. Its prime autophagy target is Atg13, a subunit of the Atg1 kinase complex that acts as the gatekeeper of canonical autophagy. To study whether the activities of TORC1 and Atg1 are coupled through additional, more intricate control mechanisms than simply this linear pathway, we analyzed the epistatic relationship between TORC1 and Atg1 by using quantitative phosphoproteomics. Our in vivo data, combined with targeted in vitro TORC1 and Atg1 kinase assays, not only uncover numerous TORC1 and Atg1 effectors, but also suggest distinct bi-directional regulatory feedback loops and characterize Atg29 as a commonly regulated downstream target of both TORC1 and Atg1. Thus, an exquisitely multilayered regulatory network appears to coordinate TORC1 and Atg1 activities to robustly tune autophagy in response to nutritional cues.
雷帕霉素复合物 1（TORC1）的靶标是细胞内稳态的主要调节剂，它促进合成代谢反应，并同步抑制自噬介导的蛋白质降解等分解代谢过程。其主要的自噬靶标是 Atg13，它是 Atg1 激酶复合物的一个亚基，作为经典自噬的“守门员”。为了研究 TORC1 和 Atg1 的活性是否通过比简单的线性途径更复杂的额外控制机制耦合，我们通过定量磷酸化蛋白质组学分析了 TORC1 和 Atg1 之间的上位关系。我们的体内数据，结合靶向的体外 TORC1 和 Atg1 激酶测定，不仅揭示了许多 TORC1 和 Atg1 的效应物，还提出了不同的双向调节反馈回路，并将 Atg29 确定为 TORC1 和 Atg1 的共同调节下游靶标。因此，一个精致的多层次调节网络似乎协调了 TORC1 和 Atg1 的活性，以响应营养信号来强有力地调节自噬。
