Translational Research Institute, Henan Provincial and Zhengzhou City Key Laboratory of Non-coding RNA and Cancer Metabolism, Henan International Join Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial People's Hospital, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
School of Environmental & Life Sciences, University of Newcastle, Callaghan, Australia.
Autophagy. 2022 Oct;18(10):2512-2513. doi: 10.1080/15548627.2022.2105557. Epub 2022 Jul 27.
Macroautophagy/autophagy is a conserved lysosome-dependent metabolic recycling pathway. ULK1 plays an essential role in autophagy initiation through a complex formed with ATG13, RB1CC1/FIP200, and ATG101 in mammalian cells. However, while autophagy is triggered by nutrient starvation where it is essential for cell survival, such conditions lead to the rapid degradation of ULK1, indicating that autophagy must be tightly controlled. Nevertheless, the precise mechanisms regulating the ULK1 complex are still largely unknown. Here we reveal the critical roles played by two novel ULK1 complex binding proteins in autophagy regulation, TRIM27 and STK38L. We show that basal autophagy is maintained through TRIM27-mediated ubiquitination and proteasomal degradation of ULK1, whereas under starvation conditions, excessive autophagy is restrained by the combined actions of TRIM27 and STK38L. TRIM27 ubiquitinates and activates STK38L which in turn phosphorylates ULK1, delivering ULK1 in a permissive state for hyper-ubiquitination by TRIM27. Thus, TRIM27 and STK38L kinase act in concert as a rheostat to control ULK1 levels. We further demonstrate increased basal autophagy in <i>trim27</i> knockout mice and establish physiological relevance in the context of breast cancer. Our study highlights the STK38L-TRIM27-ULK1 axis as a potential treatment avenue to explore for activating autophagy in various disease states.
自噬是一种保守的溶酶体依赖性代谢回收途径。在哺乳动物细胞中，ULK1 通过与 ATG13、RB1CC1/FIP200 和 ATG101 形成复合物，在自噬起始中发挥重要作用。然而，虽然自噬是由营养饥饿触发的，在这种情况下自噬对细胞存活是必不可少的，但这种条件会导致 ULK1 的快速降解，这表明自噬必须受到严格控制。然而，调节 ULK1 复合物的确切机制在很大程度上仍然未知。在这里，我们揭示了两个新的 ULK1 复合物结合蛋白在自噬调控中的关键作用，即 TRIM27 和 STK38L。我们表明，基础自噬是通过 TRIM27 介导的 ULK1 泛素化和蛋白酶体降解来维持的，而在饥饿条件下，过度的自噬受到 TRIM27 和 STK38L 的联合作用的限制。TRIM27 泛素化并激活 STK38L，后者反过来磷酸化 ULK1，使 ULK1 处于易被 TRIM27 过度泛素化的允许状态。因此，TRIM27 和 STK38L 激酶协同作用作为变阻器来控制 ULK1 水平。我们进一步证明了 <i>trim27</i> 敲除小鼠中的基础自噬增加，并在乳腺癌背景下确立了生理相关性。我们的研究强调了 STK38L-TRIM27-ULK1 轴作为一种潜在的治疗途径，可用于在各种疾病状态下激活自噬。
