Autophagy is a crucial homeostatic mechanism that mediates the degradation of damaged or excess intracellular components. Such components are engulfed and sequestered into double membrane autophagosomes, which deliver their contents to lysosomes for degradation. Autophagy plays a role in numerous human disorders and its pharmacological targeting by small molecules offers therapeutic potential. The serine/threonine kinase ULK1 (and its homologue ULK2) is the most upstream component of the autophagic machinery and is required for autophagy initiation. Here, we use the most selective and potent published ULK1 inhibitors to gain insights into ULK1 kinase function during autophagy. Treatment with all inhibitors blocked autophagy but also resulted in the limited formation of initial autophagosome-like structures, which appeared abnormal in size and did not traffic to lysosomes. We found that upon ULK1 inhibition, phosphatidylinositol-3-phosphate-binding proteins are still recruited to forming autophagosomes, implying that ULK1 activity is not essential for VPS34 activation. We conclude that the kinase activity of ULK1 is important in regulating autophagosome maturation, by the phosphorylation of currently unidentified key substrates.

中文翻译：

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小分子抑制ULK1激酶活性后，就会发生异常自噬体形成。

自噬是关键的稳态机制，其介导受损或过量的细胞内组分的降解。这些成分被吞噬并螯合成双膜自噬体，将其内容物传递至溶酶体进行降解。自噬在许多人类疾病中发挥作用，其通过小分子的药理靶向作用具有治疗潜力。丝氨酸/苏氨酸激酶ULK1（及其同系物ULK2）是自噬机制的最上游组成部分，是自噬启动所必需的。在这里，我们使用最具选择性和最有效的已发表的ULK1抑制剂来了解自噬过程中ULK1激酶的功能。用所有抑制剂处理均能阻止自噬，但也会导致初始自噬体样结构的形成受限，看起来大小不正常，没有贩运到溶酶体。我们发现在ULK1抑制后，磷脂酰肌醇-3-磷酸结合蛋白仍被募集形成自噬体，这暗示ULK1活性对于VPS34激活不是必需的。我们得出结论，通过目前未确定的关键底物的磷酸化，ULK1的激酶活性在调节自噬体成熟中很重要。