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

Nat Commun. 2015 Feb 20;6:6253. doi: 10.1038/ncomms7253.

Monika Srivastava ¹, Guowen Duan ¹, Nadia J Kershaw ², Vicki Athanasopoulos ¹, Janet H C Yeo ³, Toyoyuki Ose ⁴, Desheng Hu ⁵, Simon H J Brown ⁶, Slobodan Jergic ⁶, Hardip R Patel ⁷, Alvin Pratama ¹, Sashika Richards ¹, Anil Verma ⁴, E Yvonne Jones ⁴, Vigo Heissmeyer ⁸, Thomas Preiss ⁹, Nicholas E Dixon ⁶, Mark M W Chong ³, Jeffrey J Babon ², Carola G Vinuesa ¹

Affiliations

1 Department of Pathogens and Immunity, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia.
2 Division of Structural Biology, Walter and Eliza Hall Institute and The University of Melbourne, Melbourne, Victoria 3052, Australia.
3 Genomics and Immunology laboratory, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
4 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
5 Helmholtz Zentrum München, Institute of Molecular Immunology, D-81377 München, Germany.
6 Centre for Medical and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
7 1] Department of Genome Biology, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia [2] Genome Discovery Unit, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia.
8 1] Helmholtz Zentrum München, Institute of Molecular Immunology, D-81377 München, Germany [2] Ludwig-Maximilians-Universität München, Institute for Immunology, D-80336 München, Germany.
9 1] Department of Genome Biology, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia [2] Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.

PMID: 25697406 DOI: 10.1038/ncomms7253

Abstract

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.

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