DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions

• Autores: Wendy Huang, Benjamin Thomas, Ryan A. Flynn, Samuel J. Gavzy, Lin Wu, Sangwon V. Kim, Jason A. Hall, Emily R Miraldi, Charles P. Ng, Frank W. Rigo, Sarah Meadows, Nina R Montoya, Natalia G Herrera, Ana I Domingos, Fraydoon Rastinejad, Richard M. Myers, Frances V. Fuller-Pace, Richard Bonneau, Howard Y. Chang, Oreste Acuto, Dan R. Littman
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 528, Nº 7583, 2015, págs. 517-522
• Idioma: inglés
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• Resumen

  • T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by ROR[gamma]t, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a ROR[gamma]t partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with ROR[gamma]t and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5—ROR[gamma]t interaction and ROR[gamma]t target gene transcription. Elucidation of the link between Rmrp and the DDX5—ROR[gamma]t complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.