2. Academic Validation
  3. Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis

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

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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