The Cargo Receptor NDP52 Initiates Selective Autophagy by Recruiting the ULK Complex to Cytosol-Invading Bacteria
The Cargo Receptor NDP52 Initiates Selective Autophagy by Recruiting the ULK Complex to Cytosol-Invading Bacteria
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DOI：
10.1016/j.molcel.2019.01.041
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发表时间：
2019-04-18
期刊：
影响因子：
16
通讯作者：
Randow, Felix
中科院分区：
文献类型：
--
作者：
Ravenhill, Benjamin J.;Boyle, Keith B.;Randow, Felix
嗜异性是一种选择性的自噬途径，可以保护细胞质免受细菌入侵，它依赖于将细菌和吞噬细胞膜并列的货物受体。吞噬细胞是否从组成性库中招募或在预期货物中从头产生仍然未知。原位吞噬团的形成将需要募集上游自噬机器到预期的货物。在这里，我们表明，对于抗细菌自噬至关重要的是，货物受体NDP 52与FIP 200和SINTBAD/NAP 1形成三聚体复合物，FIP 200和SINTBAD/NAP 1分别是自噬起始ULK和TBK 1激酶复合物的亚基。FIP 200和SINTBAD/NAP 1各自通过NDP 52独立地被招募到细菌中，如在它们各自的结合位点中的选择性点突变所揭示的，但只有在它们的组合存在下，才能进行异食。NDP 52对上游自噬机制的这种募集揭示了货物相关的“吃我”信号的检测、自噬的诱导以及货物和吞噬细胞的并置是如何整合在高等真核生物中的。
Xenophagy, a selective autophagy pathway that protects the cytosol against bacterial invasion, relies on cargo receptors that juxtapose bacteria and phagophore membranes. Whether phagophores are recruited from a constitutive pool or are generated de novo at prospective cargo remains unknown. Phagophore formation in situ would require recruitment of the upstream autophagy machinery to prospective cargo. Here, we show that, essential for anti-bacterial autophagy, the cargo receptor NDP52 forms a trimeric complex with FIP200 and SINTBAD/NAP1, which are subunits of the autophagy-initiating ULK and the TBK1 kinase complex, respectively. FIP200 and SINTBAD/NAP1 are each recruited independently to bacteria via NDP52, as revealed by selective point mutations in their respective binding sites, but only in their combined presence does xenophagy proceed. Such recruitment of the upstream autophagy machinery by NDP52 reveals how detection of cargo-associated "eat me" signals, induction of autophagy, and juxtaposition of cargo and phagophores are integrated in higher eukaryotes.