Department of Medical Genetics, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Nat Chem Biol. 2021 Apr;17(4):448-455. doi: 10.1038/s41589-020-00726-x. Epub 2021 Jan 28.
Autophagy is an essential cellular process that removes harmful protein species, and autophagy upregulation may be able to protect against neurodegeneration and various pathogens. Here, we have identified the essential protein VCP/p97 (VCP, valosin-containing protein) as a novel regulator of autophagosome biogenesis, where VCP regulates autophagy induction in two ways, both dependent on Beclin-1. Utilizing small-molecule inhibitors of VCP ATPase activity, we show that VCP stabilizes Beclin-1 levels by promoting the deubiquitinase activity of ataxin-3 towards Beclin-1. VCP also regulates the assembly and activity of the Beclin-1-containing phosphatidylinositol-3-kinase (PI3K) complex I, thus regulating the production of PI(3)P, a key signaling lipid responsible for the recruitment of downstream autophagy factors. A decreased level of VCP, or inhibition of its ATPase activity, impairs starvation-induced production of PI(3)P and limits downstream recruitment of WIPI2, ATG16L and LC3, thereby decreasing autophagosome formation, illustrating an important role for VCP in early autophagy initiation.
自噬是一种重要的细胞过程，它可以清除有害的蛋白质种类，而自噬的上调可能能够保护免受神经退行性变和各种病原体的侵害。在这里，我们已经确定了必需的蛋白 VCP/p97（VCP，含 valosin 蛋白）作为自噬体生物发生的新型调节剂，其中 VCP 通过两种方式调节自噬诱导，这两种方式都依赖于 Beclin-1。利用 VCP ATP 酶活性的小分子抑制剂，我们表明 VCP 通过促进 ataxin-3 对 Beclin-1 的去泛素化酶活性来稳定 Beclin-1 水平。VCP 还调节含有 Beclin-1 的磷酸肌醇 3-激酶（PI3K）复合物 I 的组装和活性，从而调节 PI(3)P 的产生，PI(3)P 是一种关键的信号脂质，负责募集下游自噬因子。VCP 水平降低或其 ATP 酶活性受到抑制，会损害饥饿诱导的 PI(3)P 的产生，并限制 WIPI2、ATG16L 和 LC3 的下游募集，从而减少自噬体的形成，这说明了 VCP 在早期自噬起始中的重要作用。
