The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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.
EMBO J. 2022 Jul 18;41(14):e109777. doi: 10.15252/embj.2021109777. Epub 2022 Jun 7.
Autophagy represents a fundamental mechanism for maintaining cell survival and tissue homeostasis in response to physiological and pathological stress. Autophagy initiation converges on the FIP200-ATG13-ULK1 complex wherein the serine/threonine kinase ULK1 plays a central role. Here, we reveal that the E3 ubiquitin ligase TRIM27 functions as a negative regulatory component of the FIP200-ATG13-ULK1 complex. TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels. However, during starvation-induced autophagy, TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1. This cooperative mechanism serves to restrain the amplitude and duration of autophagy. Further evidence from mouse models shows that basal autophagy levels are increased in Trim27 knockout mice and that Trim27 differentially regulates tumorigenesis and metastasis. Our study identifies a key role of STK38L-TRIM27-ULK1 signaling axis in negatively controlling autophagy with relevance established in human breast cancer.
自噬是细胞在生理和病理应激下维持生存和组织内稳态的基本机制。自噬的起始集中在 FIP200-ATG13-ULK1 复合物上，丝氨酸/苏氨酸激酶 ULK1 在此复合物中发挥核心作用。在这里，我们揭示 E3 泛素连接酶 TRIM27 作为 FIP200-ATG13-ULK1 复合物的负调控组件发挥作用。TRIM27 直接在 K568 和 K571 位点对 ULK1 进行多泛素化，形成 K48 连接的泛素链，蛋白酶体降解控制着基础 ULK1 水平。然而，在饥饿诱导的自噬中，TRIM27 催化丝氨酸/苏氨酸激酶 38 样（STK38L）激酶的非降解 K6 和 K11 连接的泛素化。反过来，STK38L 泛素化促进其对 ULK1 的 Ser495 的激活和磷酸化，使 ULK1 处于 TRIM27 介导的 ULK1 过度泛素化的许可状态。这种协同机制有助于限制自噬的幅度和持续时间。来自小鼠模型的进一步证据表明，Trim27 敲除小鼠的基础自噬水平增加，Trim27 差异调节肿瘤发生和转移。我们的研究确定了 STK38L-TRIM27-ULK1 信号轴在负性控制自噬中的关键作用，在人类乳腺癌中建立了相关性。
