Medicine (St Vincent's) - Research Publications

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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 (NATURE PUBLISHING GROUP, 2015-02)

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.