title: Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis.
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.
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Monika
authors.initials: M
authors.lastname: Srivastava
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Guowen
authors.initials: G
authors.lastname: Duan
authors.affiliation: Division of Structural Biology, Walter and Eliza Hall Institute and The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Nadia J
authors.initials: NJ
authors.lastname: Kershaw
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Vicki
authors.initials: V
authors.lastname: Athanasopoulos
authors.affiliation: Genomics and Immunology laboratory, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Janet H C
authors.initials: JH
authors.lastname: Yeo
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Toyoyuki
authors.initials: T
authors.lastname: Ose
authors.affiliation: Helmholtz Zentrum München, Institute of Molecular Immunology, D-81377 München, Germany.
authors.forename: Desheng
authors.identifier: 0000000206463968
authors.initials: D
authors.lastname: Hu
authors.affiliation: Centre for Medical and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Simon H J
authors.initials: SH
authors.lastname: Brown
authors.affiliation: Centre for Medical and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Jergic
authors.affiliation: 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.
authors.forename: Hardip R
authors.initials: HR
authors.lastname: Patel
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Alvin
authors.initials: A
authors.lastname: Pratama
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Sashika
authors.initials: S
authors.lastname: Richards
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Anil
authors.initials: A
authors.lastname: Verma
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.affiliation: 1] Helmholtz Zentrum München, Institute of Molecular Immunology, D-81377 München, Germany [2] Ludwig-Maximilians-Universität München, Institute for Immunology, D-80336 München, Germany.
authors.forename: Vigo
authors.initials: V
authors.lastname: Heissmeyer
authors.affiliation: 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.
authors.forename: Thomas
authors.identifier: 000000016273784X
authors.initials: T
authors.lastname: Preiss
authors.affiliation: Centre for Medical and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Nicholas E
authors.identifier: 0000000259586945
authors.initials: NE
authors.lastname: Dixon
authors.affiliation: Genomics and Immunology laboratory, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Mark M W
authors.initials: MM
authors.lastname: Chong
authors.affiliation: Division of Structural Biology, Walter and Eliza Hall Institute and The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Jeffrey J
authors.identifier: 0000000254086239
authors.initials: JJ
authors.lastname: Babon
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism*; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006207:Half-Life; D006706:Homeostasis; D006801:Humans; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D043244:Ribonuclease III / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*
chemical_list: C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D043244:Ribonuclease III