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Roquin recognizes a non-canonical hexaloop structure in the 3′-UTR of Ox40


Janowski, Robert; Heinz, Gitta A; Schlundt, Andreas; Wommelsdorf, Nina; Brenner, Sven; Gruber, Andreas R; Blank, Michael; Buch, Thorsten; Buhmann, Raymund; Zavolan, Mihaela; Niessing, Dierk; Heissmeyer, Vigo; Sattler, Michael (2016). Roquin recognizes a non-canonical hexaloop structure in the 3′-UTR of Ox40. Nature Communications, 7:11032.

Abstract

The RNA-binding protein Roquin is required to prevent autoimmunity. Roquin controls T-helper cell activation and differentiation by limiting the induced expression of costimulatory receptors such as tumor necrosis factor receptor superfamily 4 (Tnfrs4 or Ox40). A constitutive decay element (CDE) with a characteristic triloop hairpin was previously shown to be recognized by Roquin. Here we use SELEX assays to identify a novel U-rich hexaloop motif, representing an alternative decay element (ADE). Crystal structures and NMR data show that the Roquin-1 ROQ domain recognizes hexaloops in the SELEX-derived ADE and in an ADE-like variant present in the Ox40 3'-UTR with identical binding modes. In cells, ADE-like and CDE-like motifs cooperate in the repression of Ox40 by Roquin. Our data reveal an unexpected recognition of hexaloop cis elements for the posttranscriptional regulation of target messenger RNAs by Roquin.

Abstract

The RNA-binding protein Roquin is required to prevent autoimmunity. Roquin controls T-helper cell activation and differentiation by limiting the induced expression of costimulatory receptors such as tumor necrosis factor receptor superfamily 4 (Tnfrs4 or Ox40). A constitutive decay element (CDE) with a characteristic triloop hairpin was previously shown to be recognized by Roquin. Here we use SELEX assays to identify a novel U-rich hexaloop motif, representing an alternative decay element (ADE). Crystal structures and NMR data show that the Roquin-1 ROQ domain recognizes hexaloops in the SELEX-derived ADE and in an ADE-like variant present in the Ox40 3'-UTR with identical binding modes. In cells, ADE-like and CDE-like motifs cooperate in the repression of Ox40 by Roquin. Our data reveal an unexpected recognition of hexaloop cis elements for the posttranscriptional regulation of target messenger RNAs by Roquin.

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Contributors:Arie Geerlof for providing recombinant T7 enzyme, X-ray crystallography platform, the protein expression and purification facility of the Helmholtz Zentrum München and the Bavarian NMR Center
Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Laboratory Animal Science
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:24 March 2016
Deposited On:19 Apr 2016 16:37
Last Modified:08 Dec 2017 19:23
Publisher:Nature Publishing Group
ISSN:2041-1723
Funders:Boehringer Ingelheim Fonds for a PhD fellowship, Deutsche Forschungsgemeinschaft, European Commission through a European Research Council grant
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/ncomms11032
PubMed ID:27010430

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