Iruka Eliminates Dysfunctional Argonaute by Selective Ubiquitination of Its Empty State
Iruka Eliminates Dysfunctional Argonaute by Selective Ubiquitination of Its Empty State
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DOI：
10.1016/j.molcel.2018.10.033
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发表时间：
2019-01-03
期刊：
影响因子：
16
通讯作者：
Tomari, Yukihide
中科院分区：
文献类型：
--
作者：
Kobayashi, Hotaka;Shoji, Keisuke;Tomari, Yukihide
微小RNA（miRNAs）被加载到Argonaute蛋白亚家族（AGO）中以形成使靶基因沉默的效应复合物。空的但不是miRNA负载的AGO在物种间选择性降解。然而，AGO选择性降解的机制和生物学意义尚不清楚。我们发现了一种RING型E3泛素连接酶，我们将其命名为Iruka（Iru），它选择性地泛素化果蝇Ago 1的空形式，以引发其降解。Iru优先结合空的Ago 1，并泛素化L2接头中的Lys 514，这被预测为在miRNA负载状态下不可接近。Iru的缺失导致靶基因的miRNA介导的沉默的整体损害和异常Ago 1的积累，其对于典型的蛋白质-蛋白质相互作用和miRNA加载是功能失调的。我们的研究结果揭示了一个复杂的机制，空AGO的选择性降解的质量控制过程，以确保AGO功能的基础。
MicroRNAs (miRNAs) are loaded into the Argonaute subfamily of proteins (AGO) to form an effector complex that silences target genes. Empty but not miRNA-loaded AGO is selectively degraded across species. However, the mechanism and biological significance of selective AGO degradation remain unclear. We discovered a RING-type E3 ubiquitin ligase we named Iruka (Iru), which selectively ubiquitinates the empty form of Drosophila Ago1 to trigger its degradation. Iru preferentially binds empty Ago1 and ubiquitinates Lys514 in the L2 linker, which is predicted to be inaccessible in the miRNA-loaded state. Depletion of Iru results in global impairment of miRNA-mediated silencing of target genes and in the accumulation of aberrant Ago1 that is dysfunctional for canonical protein-protein interactions and miRNA loading. Our findings reveal a sophisticated mechanism for the selective degradation of empty AGO that underlies a quality control process to ensure AGO function.