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Mol Cell. 2019 Jan 3;73(1):119-129.e5. doi: 10.1016/j.molcel.2018.10.033. Epub 2018 Nov 29.

Iruka Eliminates Dysfunctional Argonaute by Selective Ubiquitination of Its Empty State.

Author information

1
Laboratory of RNA Function, Institute for Quantitative Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: hota-koba@iam.u-tokyo.ac.jp.
2
Laboratory of RNA Function, Institute for Quantitative Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; Department of Agrobiology and Bioresources, School of Agriculture, Utsunomiya University, Utsunomiya, Tochigi 321-8505, Japan.
3
Laboratory of RNA Function, Institute for Quantitative Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
4
Central Laboratory, Institute for Quantitative Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
5
Laboratory of RNA Function, Institute for Quantitative Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: tomari@iam.u-tokyo.ac.jp.

Abstract

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.

KEYWORDS:

E3 ubiquitin ligase; Iruka; RNA silencing; argonaute; microRNA; protein quality control; ubiquitin

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