Institute for Biochemistry and Molecular Medicine, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
Autophagy. 2013 Jun 1;9(6):933-5. doi: 10.4161/auto.24390. Epub 2013 Apr 4.
We have elucidated a novel mechanism through which the autophagy-specific class III phosphatidylinositol 3-kinase (PtdIns3K) complex can be recruited to the PAS in mammalian cells, through the interaction between BECN1 and the vacuole membrane protein 1 (VMP1), an integral autophagosomal membrane protein. This interaction involves the binding between the C-terminal 20 amino acids of the VMP1 hydrophilic domain, which we have named the VMP1 autophagy-related domain (VMP1-AtgD), and the BH3 domain of BECN1. The association between these two proteins allows the formation of the autophagy-specific PtdIns3K complex, which activity favors the generation of phosphatidylinositol-3-phosphate (PtdIns3P) and the subsequent association of the autophagy-related (ATG) proteins, including ATG16L1, with the phagophore membranes. Therefore, VMP1 regulates the PtdIns3K activity on the phagophore membrane through its interaction with BECN1. Our data provide a novel model describing one of the key steps in phagophore assembly site (PAS) formation and autophagy regulation, and positions VMP1 as a new interactor of the autophagy-specific PtdIns3K complex in mammalian cells.
我们阐明了一种新的机制，通过该机制，自噬特异性 III 类磷脂酰肌醇 3-激酶（PtdIns3K）复合物可以通过 BECN1 与液泡膜蛋白 1（VMP1）相互作用而被募集到哺乳动物细胞的 PAS 中，VMP1 是一种完整的自噬体膜蛋白。这种相互作用涉及到 VMP1 亲水结构域的 C 末端 20 个氨基酸与 BECN1 的 BH3 结构域之间的结合，我们将其命名为 VMP1 自噬相关结构域（VMP1-AtgD）。这两种蛋白质之间的结合允许形成自噬特异性 PtdIns3K 复合物，其活性有利于磷脂酰肌醇-3-磷酸（PtdIns3P）的生成，随后自噬相关（ATG）蛋白，包括 ATG16L1，与吞噬体膜结合。因此，VMP1 通过与 BECN1 的相互作用来调节吞噬体膜上的 PtdIns3K 活性。我们的数据提供了一个新的模型，描述了吞噬体组装位点（PAS）形成和自噬调节的关键步骤之一，并将 VMP1 定位为哺乳动物细胞中自噬特异性 PtdIns3K 复合物的新相互作用因子。
