| Structural highlights
Function
[RC3H1_MOUSE] Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3'-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF and in many more mRNAs (PubMed:23663784). Binds to CDE and promotes mRNA deadenylation and degradation. This process does not involve miRNAs. In follicular helper T (Tfh) cells, represses of ICOS and TNFRSF4/Ox40 expression, thus preventing spontaneous Tfh cell differentiation, germinal center B-cell differentiation in the absence of immunization and autoimmunity. In resting or LPS-stimulated macrophages, controls inflammation by suppressing TNF expression. Also recognizes CDE in its own mRNA and in that of paralogous RC3H2, possibly leading to feedback loop regulation.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
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.
Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40.,Janowski R, Heinz GA, Schlundt A, Wommelsdorf N, Brenner S, Gruber AR, Blank M, Buch T, Buhmann R, Zavolan M, Niessing D, Heissmeyer V, Sattler M Nat Commun. 2016 Mar 24;7:11032. doi: 10.1038/ncomms11032. PMID:27010430[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM, Yu D, Domaschenz H, Whittle B, Lambe T, Roberts IS, Copley RR, Bell JI, Cornall RJ, Goodnow CC. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature. 2005 May 26;435(7041):452-8. PMID:15917799 doi:http://dx.doi.org/10.1038/nature03555
- ↑ Yu D, Tan AH, Hu X, Athanasopoulos V, Simpson N, Silva DG, Hutloff A, Giles KM, Leedman PJ, Lam KP, Goodnow CC, Vinuesa CG. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature. 2007 Nov 8;450(7167):299-303. doi: 10.1038/nature06253. PMID:18172933 doi:http://dx.doi.org/10.1038/nature06253
- ↑ Athanasopoulos V, Barker A, Yu D, Tan AH, Srivastava M, Contreras N, Wang J, Lam KP, Brown SH, Goodnow CC, Dixon NE, Leedman PJ, Saint R, Vinuesa CG. The ROQUIN family of proteins localizes to stress granules via the ROQ domain and binds target mRNAs. FEBS J. 2010 May;277(9):2109-27. doi: 10.1111/j.1742-4658.2010.07628.x. PMID:20412057 doi:http://dx.doi.org/10.1111/j.1742-4658.2010.07628.x
- ↑ Glasmacher E, Hoefig KP, Vogel KU, Rath N, Du L, Wolf C, Kremmer E, Wang X, Heissmeyer V. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat Immunol. 2010 Aug;11(8):725-33. doi: 10.1038/ni.1902. Epub 2010 Jul 18. PMID:20639877 doi:http://dx.doi.org/10.1038/ni.1902
- ↑ Leppek K, Schott J, Reitter S, Poetz F, Hammond MC, Stoecklin G. Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell. 2013 May 9;153(4):869-81. doi: 10.1016/j.cell.2013.04.016. PMID:23663784 doi:http://dx.doi.org/10.1016/j.cell.2013.04.016
- ↑ Vogel KU, Edelmann SL, Jeltsch KM, Bertossi A, Heger K, Heinz GA, Zoller J, Warth SC, Hoefig KP, Lohs C, Neff F, Kremmer E, Schick J, Repsilber D, Geerlof A, Blum H, Wurst W, Heikenwalder M, Schmidt-Supprian M, Heissmeyer V. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity. 2013 Apr 18;38(4):655-68. doi: 10.1016/j.immuni.2012.12.004. Epub 2013 , Apr 11. PMID:23583643 doi:http://dx.doi.org/10.1016/j.immuni.2012.12.004
- ↑ Pratama A, Ramiscal RR, Silva DG, Das SK, Athanasopoulos V, Fitch J, Botelho NK, Chang PP, Hu X, Hogan JJ, Mana P, Bernal D, Korner H, Yu D, Goodnow CC, Cook MC, Vinuesa CG. Roquin-2 shares functions with its paralog Roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation. Immunity. 2013 Apr 18;38(4):669-80. doi: 10.1016/j.immuni.2013.01.011. Epub 2013 , Apr 11. PMID:23583642 doi:http://dx.doi.org/10.1016/j.immuni.2013.01.011
- ↑ Janowski R, Heinz GA, Schlundt A, Wommelsdorf N, Brenner S, Gruber AR, Blank M, Buch T, Buhmann R, Zavolan M, Niessing D, Heissmeyer V, Sattler M. Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40. Nat Commun. 2016 Mar 24;7:11032. doi: 10.1038/ncomms11032. PMID:27010430 doi:http://dx.doi.org/10.1038/ncomms11032
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