Autophagy is a highly conserved catabolic process through which defective or otherwise harmful cellular components are targeted for degradation via the lysosomal route. Regulatory pathways, involving post-translational modifications such as phosphorylation, play a critical role in controlling this tightly orchestrated process. Here, we demonstrate that TBK1 regulates autophagy by phosphorylating autophagy modifiers LC3C and GABARAP-L2 on surface-exposed serine residues (LC3C S93 and S96; GABARAP-L2 S87 and S88). This phosphorylation event impedes their binding to the processing enzyme ATG4 by destabilizing the complex. Phosphorylated LC3C/GABARAP-L2 cannot be removed from liposomes by ATG4 and are thus protected from ATG4-mediated premature removal from nascent autophagosomes. This ensures a steady coat of lipidated LC3C/GABARAP-L2 throughout the early steps in autophagosome formation and aids in maintaining a unidirectional flow of the autophagosome to the lysosome. Taken together, we present a new regulatory mechanism of autophagy, which influences the conjugation and de-conjugation of LC3C and GABARAP-L2 to autophagosomes by TBK1-mediated phosphorylation.

中文翻译：

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TBK1 介导的 LC3C 和 GABARAP-L2 磷酸化控制 ATG4 蛋白酶的自噬体脱落。

自噬是一个高度保守的分解代谢过程，通过该过程有缺陷或其他有害的细胞成分通过溶酶体途径被靶向降解。涉及翻译后修饰（如磷酸化）的调节途径在控制这一紧密协调的过程中发挥着关键作用。在这里，我们证明 TBK1 通过磷酸化表面暴露的丝氨酸残基（LC3C S93 和 S96；GABARAP-L2 S87 和 S88）上的自噬修饰剂 LC3C 和 GABARAP-L2 来调节自噬。这种磷酸化事件通过破坏复合物的稳定性来阻止它们与加工酶 ATG4 的结合。磷酸化的 LC3C/GABARAP-L2 不能被 ATG4 从脂质体中去除，因此可以防止 ATG4 介导的从新生自噬体中过早去除。这确保了在自噬体形成的早期步骤中稳定的脂化 LC3C/GABARAP-L2 涂层，并有助于维持自噬体向溶酶体的单向流动。总之，我们提出了一种新的自噬调节机制，它通过 TBK1 介导的磷酸化影响 LC3C 和 GABARAP-L2 与自噬体的结合和去结合。