Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, United States.
Perlmutter NYU Cancer Center, NYU School of Medicine, New York, United States.
Elife. 2018 Dec 31;7:e42253. doi: 10.7554/eLife.42253.
In response to nutrient deprivation, the cell mobilizes an extensive amount of membrane to form and grow the autophagosome, allowing the progression of autophagy. By providing membranes and stimulating LC3 lipidation, COPII (Coat Protein Complex II) promotes autophagosome biogenesis. Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation. Phosphorylated and stabilized SEC23B associates with SEC24A and SEC24B, but not SEC24C and SEC24D, and they re-localize to the ER-Golgi intermediate compartment, promoting autophagic flux. We propose that, in the presence of nutrients, FBXW5 limits COPII-mediated autophagosome biogenesis. Inhibition of this event by ULK1 ensures efficient execution of the autophagic cascade in response to nutrient starvation.
在营养缺乏的情况下，细胞会动员大量的膜来形成和生长自噬体，从而促进自噬的进行。COPII（衣被蛋白复合物 II）通过提供膜并刺激 LC3 脂质化来促进自噬体的生物发生。在这里，我们表明 F-box 蛋白 FBXW5 将 COPII 的组成部分 SEC23B 靶向到蛋白酶体进行降解，并且在存在营养物质的情况下，这一事件限制了自噬通量。在饥饿反应中，ULK1 磷酸化 SEC23B 的丝氨酸 186，阻止 SEC23B 与 FBXW5 的相互作用，从而抑制 SEC23B 的降解。磷酸化和稳定的 SEC23B 与 SEC24A 和 SEC24B 结合，但不与 SEC24C 和 SEC24D 结合，它们重新定位到 ER-Golgi 中间隔室，促进自噬通量。我们提出，在存在营养物质的情况下，FBXW5 限制了 COPII 介导的自噬体生物发生。ULK1 抑制这一事件可确保在营养饥饿时有效地执行自噬级联反应。
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