VCP Machinery Mediates Autophagic Degradation of Empty Argonaute
VCP Machinery Mediates Autophagic Degradation of Empty Argonaute
复制标题
DOI：
10.1016/j.celrep.2019.07.003
复制
发表时间：
2019-07-30
期刊：
影响因子：
8.8
通讯作者：
Tomari, Yukihide
中科院分区：
文献类型：
--
作者：
Kobayashi, Hotaka;Shoji, Keisuke;Tomari, Yukihide
Argonaute蛋白亚家族（AGO）装载microRNA（miRNA）以形成介导靶基因沉默的效应子复合物。空的AGO，而不是miRNA加载的AGO，在物种间选择性降解。我们已经报道了空AGO的降解是消除功能失调的AGO的质量控制途径的一部分。然而，空AGO如何降解仍不清楚。在这里，我们表明，空状态的果蝇Ago 1被自噬降解。全面的LC-MS/MS分析，连同Ago 1泛素化水平的操作，揭示了介导选择性自噬的VCP通过Ufd 1-Npl 4异二聚体识别空Ago 1。VCP-Ufd 1-Npl 4机制的消耗损害空Ago 1的降解和miRNA介导的靶基因沉默。我们的发现揭示了空AGO降解和选择性自噬之间的直接联系，从而确保了有效的miRNA功能。
The Argonaute subfamily of proteins (AGO) loads microRNAs (miRNAs) to form the effector complex that mediates target gene silencing. Empty AGO, but not miRNA-loaded AGO, is selectively degraded across species. We have reported that the degradation of empty AGO is part of a quality control pathway that eliminates dysfunctional AGO. However, how empty AGO is degraded remains unclear. Here we show that the empty state of Drosophila Ago1 is degraded by autophagy. Comprehensive LC-MS/MS analyses, together with manipulation of the Ago1 ubiquitination level, revealed that VCP, which mediates selective autophagy, recognizes empty Ago1 via the Ufd1-Npl4 heterodimer. Depletion of VCP-Ufd1-Npl4 machinery impairs degradation of empty Ago1 and miRNA-mediated target gene silencing. Our findings reveal a direct link between empty AGO degradation and selective autophagy that ensures efficient miRNA function.