Roquin Promotes Constitutive mRNA Decay via a Conserved Class of Stem-Loop Recognition Motifs

Tumor necrosis factor-a (TNF-a) is the most potent proinflammatory cytokine in mammals. The degradation of TNF-a mRNA is critical for restricting TNF-a synthesis and involves a constitutive decay element (CDE) in the 30 UTR of the mRNA. Here, we demonstrate that the CDE folds into an RNA stem-loop motif that is specifically recognized by Roquin and Roquin2. Binding of Roquin initiates degradation of TNF-a mRNA and limits TNF-a production in macrophages. Roquin proteins promote mRNA degradation by recruiting the Ccr4-Caf1-Not deadenylase complex. CDE sequences are highly conserved and are found in more than 50 vertebrate mRNAs, many of which encode regulators of development and inflammation. In macrophages, CDE-containing mRNAs were identified as the primary targets of Roquin on a transcriptome-wide scale. Thus, Roquin proteins act broadly as mediators of mRNA deadenylation by recognizing a conserved class of stem-loop RNA degradation motifs.