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Roquin is an RNA-binding protein that prevents autoimmunity and inflammation via repression of bound target mRNAs such as inducible costimulator (Icos). When Roquin is absent or mutated (Roquin(san)), Icos is overexpressed in T cells. Here we show that Roquin enhances Dicer-mediated processing of pre-miR-146a. Roquin also directly binds Argonaute2, a central component of the RNA-induced silencing complex, and miR-146a, a microRNA that targets Icos mRNA. In the absence of functional Roquin, miR-146a accumulates in T cells. Its accumulation is not due to increased transcription or processing, rather due to enhanced stability of mature miR-146a. This is associated with decreased 3' end uridylation of the miRNA. Crystallographic studies reveal that Roquin contains a unique HEPN domain and identify the structural basis of the 'san' mutation and Roquin's ability to bind multiple RNAs. Roquin emerges as a protein that can bind Ago2, miRNAs and target mRNAs, to control homeostasis of both RNA species.

Original publication

DOI

10.1038/ncomms7253

Type

Journal article

Journal

Nat Commun

Publication Date

20/02/2015

Volume

6

Keywords

Animals, Argonaute Proteins, Crystallography, X-Ray, HEK293 Cells, Half-Life, Homeostasis, Humans, Mice, Inbred C57BL, MicroRNAs, Protein Binding, Protein Structure, Tertiary, RNA Processing, Post-Transcriptional, RNA Stability, Ribonuclease III, T-Lymphocytes, Ubiquitin-Protein Ligases