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.