Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis

• Published in: Nature communications Vol. 6; no. 1; p. 6253
• Main Authors: Srivastava, Monika, Duan, Guowen, Kershaw, Nadia J., Athanasopoulos, Vicki, Yeo, Janet H. C., Ose, Toyoyuki, Hu, Desheng, Brown, Simon H. J., Jergic, Slobodan, Patel, Hardip R., Pratama, Alvin, Richards, Sashika, Verma, Anil, Jones, E. Yvonne, Heissmeyer, Vigo, Preiss, Thomas, Dixon, Nicholas E., Chong, Mark M. W., Babon, Jeffrey J., Vinuesa, Carola G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.02.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 13; 13/1; 13/106; 13/109; 13/31; 13/44; 13/51; 14/19; 14/63; 38/22; 38/32; 38/39; 38/61; 38/90; 38/91; 631/250/1619/554/1898/1270; 631/337/384/331; 631/45/612/1230; 64/60; 82/103; 82/6; 82/83; Animals; Argonaute Proteins - metabolism; Bone marrow; Crystallography, X-Ray; Genomes; Half-Life; HEK293 Cells; Homeostasis; Humanities and Social Sciences; Humans; Immunology; Localization; Lymphocytes; Medical research; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; multidisciplinary; Mutation; Protein Binding - genetics; Protein Structure, Tertiary; Proteins; Ribonuclease III - metabolism; RNA Processing, Post-Transcriptional; RNA Stability; Science; Science (multidisciplinary); T-Lymphocytes - metabolism; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism; Australia; Canberra Australian Capital Territory Australia; Germany; Australian Capital Territory Australia; New South Wales Australia
• DOI: 10.1038/ncomms7253
• ISSN: 2041-1723

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. Roquin is an RNA-binding protein that promotes the degradation of specific mRNAs and is crucial for the maintenance of peripheral immune tolerance. Here the authors show that, in addition to its target mRNAs, Roquin can bind miR-146a and the RISC component Ago2 to control homeostasis of both RNA species.