Resumen de DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions
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
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.
