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

Monika Srivastava, Guowen Duan, Nadia J. Kershaw, Vicki Athanasopoulos, Janet H. C. Yeo, Toyoyuki Ose, Desheng Hu, Simon H. J. Brown, Slobodan Jergic, Hardip R. Patel, Alvin Pratama, Sashika Richards, Anil Verma, E. Yvonne Jones, Vigo Heissmeyer, Thomas Preiss, Nicholas E. Dixon, Mark M. W. Chong, Jeffrey J. Babon and Carola G. Vinuesa ()
Additional contact information
Monika Srivastava: John Curtin School of Medical Research
Guowen Duan: John Curtin School of Medical Research
Nadia J. Kershaw: Walter and Eliza Hall Institute and The University of Melbourne
Vicki Athanasopoulos: John Curtin School of Medical Research
Janet H. C. Yeo: Genomics and Immunology laboratory, St Vincent’s Institute of Medical Research
Toyoyuki Ose: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
Desheng Hu: Helmholtz Zentrum München, Institute of Molecular Immunology
Simon H. J. Brown: Centre for Medical and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute
Slobodan Jergic: Centre for Medical and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute
Hardip R. Patel: John Curtin School of Medical Research
Alvin Pratama: John Curtin School of Medical Research
Sashika Richards: John Curtin School of Medical Research
Anil Verma: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
E. Yvonne Jones: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
Vigo Heissmeyer: Helmholtz Zentrum München, Institute of Molecular Immunology
Thomas Preiss: John Curtin School of Medical Research
Nicholas E. Dixon: Centre for Medical and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute
Mark M. W. Chong: Genomics and Immunology laboratory, St Vincent’s Institute of Medical Research
Jeffrey J. Babon: Walter and Eliza Hall Institute and The University of Melbourne
Carola G. Vinuesa: John Curtin School of Medical Research

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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 (Roquinsan), 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.

Date: 2015
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DOI: 10.1038/ncomms7253

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