Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis.
Srivastava M., Duan G., Kershaw NJ., Athanasopoulos V., Yeo JHC., Ose T., Hu D., Brown SHJ., Jergic S., Patel HR., Pratama A., Richards S., Verma A., Jones EY., Heissmeyer V., Preiss T., Dixon NE., Chong MMW., Babon JJ., Vinuesa CG.
Roquin is an RNA-binding protein that prevents autoimmunity and inflammation via repression of bound target mRNAs such as inducible costimulator (Icos). When Roquin is absent or mutated (Roquin(san)), Icos is overexpressed in T cells. Here we show that Roquin enhances Dicer-mediated processing of pre-miR-146a. Roquin also directly binds Argonaute2, a central component of the RNA-induced silencing complex, and miR-146a, a microRNA that targets Icos mRNA. In the absence of functional Roquin, miR-146a accumulates in T cells. Its accumulation is not due to increased transcription or processing, rather due to enhanced stability of mature miR-146a. This is associated with decreased 3' end uridylation of the miRNA. Crystallographic studies reveal that Roquin contains a unique HEPN domain and identify the structural basis of the 'san' mutation and Roquin's ability to bind multiple RNAs. Roquin emerges as a protein that can bind Ago2, miRNAs and target mRNAs, to control homeostasis of both RNA species.