Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex
Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex
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DOI：
10.1073/pnas.1811874115
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发表时间：
2018-10-16
影响因子：
11.1
通讯作者：
Otomo, Takanori
中科院分区：
文献类型：
--
作者：
Chowdhury, Saikat;Otomo, Chinatsu;Otomo, Takanori
自噬是一种神秘的细胞过程，称为自噬体的双膜室在内质网（ER）附近重新形成，并包装细胞质内容物以传递给溶酶体。前体细胞膜吞噬细胞的扩张需要自噬相关的2 (ATG2)，其定位于pi3p富集的er -吞噬细胞连接处。我们结合单粒子电子显微镜、化学交联联用质谱和生化分析来表征人类ATG2A与PI3P效应物WIPI4的复合物。ATG2A是一种杆状蛋白质，可以通过其每个尖端的相互作用架起相邻囊泡的桥梁。WIPI4与其中一个尖端结合，使ATG2A-WIPI4复合物能够将含有pi3p的囊泡连接到另一个不含pi3p的囊泡上。这些数据表明，ATG2A-WIPI4复合物介导ER-吞噬细胞结合和/或将囊泡系在ER-吞噬细胞连接处，通过脂质膜从ER和/或囊泡转移到吞噬细胞，建立了吞噬细胞扩张所需的组织。
Autophagy is an enigmatic cellular process in which double-membrane compartments, called "autophagosomes, form de novo adjacent to the endoplasmic reticulum (ER) and package cytoplasmic contents for delivery to lysosomes. Expansion of the precursor membrane phagophore requires autophagy-related 2 (ATG2), which localizes to the PI3P-enriched ER-phagophore junction. We combined single-particle electron microscopy, chemical cross-linking coupled with mass spectrometry, and biochemical analyses to characterize human ATG2A in complex with the PI3P effector WIPI4. ATG2A is a rod-shaped protein that can bridge neighboring vesicles through interactions at each of its tips. WIPI4 binds to one of the tips, enabling the ATG2A-WIPI4 complex to tether a PI3P-containing vesicle to another PI3P-free vesicle. These data suggest that the ATG2A-WIPI4 complex mediates ER-phagophore association and/or tethers vesicles to the ER-phagophore junction, establishing the required organization for phagophore expansion via the transfer of lipid membranes from the ER and/or the vesicles to the phagophore.