Editors' ChoiceImmunology

Noncoding RNA plugs into a proinflammatory circuit

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Science Translational Medicine  13 Jan 2016:
Vol. 8, Issue 321, pp. 321ec7
DOI: 10.1126/scitranslmed.aaf0855

A subset of CD4+ T cells, T helper 17 (TH17) cells contribute to multiple human autoimmune diseases. Intensive efforts are under way to pinpoint new therapeutic targets to inhibit TH17-driven tissue inflammation. The nuclear receptor RORγt is an essential transcriptional regulator for TH17 cell differentiation and function. Littman and colleagues set out to identify molecular partners of RORγt that could be targeted to tune down the pathogenic effects of TH17 cells and discovered a complex that included, not only proteins, but also a long noncoding RNA (lncRNA), Rmrp. Thousands of lncRNAs have been identified in recent years—including lncRNAs expressed in immune cells—but the molecular functions of most remain unknown. This study provides mechanistic insight into how a lncRNA can partner with a regulator of cell identity to control a key gene expression program.

The authors initially performed an unbiased search for protein partners of RORγt using mass spectroscopy. The RNA helicase DDX5 was identified and found to be essential for proper regulation of a set of RORγt target genes. DDX5 deficiency in T cells reduced the severity of TH17-mediated inflammation in mouse models of inflammatory bowel disease and multiple sclerosis. DDX5 regulation of TH17 function was dependent on its RNA-helicase domain, leading the authors to speculate that DDX5 might have an essential interaction with an RNA molecule in addition to its protein partners. To follow this lead, they precipitated RNA species associated with DDX5 and RORγt and subjected these transcripts to deep sequencing. The Rmrp lncRNA was bound to both proteins. Biochemical studies in vitro and in genetically modified mice characterized how the lncRNA complexes with DDX5 and RORγt at specific chromatin loci where it is essential for proper TH17 cell gene regulation.

This study integrates multiple technologies to dissect gene regulatory mechanisms of a noncoding RNA. The identified Rmrp-DDX5-RORγt complex, which interacts with key genomic sites to promote TH17 function, could represent a new therapeutic target for autoimmune diseases. The authors suggest that targeting the Rmrp-DDX5-RORγt complex might be a strategy to specifically modulate pathogenic TH17 cell transcriptional circuits, although DDX5 and Rmrp­ are both expressed in diverse cell types. Future efforts will be required to test whether new therapies can disrupt the complex in TH17 cells while minimizing side effects in other cell types. The published study provides a biochemical framework for how RNA-protein complexes may be considered therapeutic targets for human autoimmune diseases.

W. Huang et al., DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature 528, 517–522 (2015). [Full Text]

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