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

• CDEs represent a class of conserved RNA stem loops
• Roquin and Roquin2 bind with high specificity to the CDE stem loop
• Roquin causes mRNA deadenylation by recruitment of the Ccr4-Caf1-Not complex
• In macrophages, Roquin limits TNF-α production via CDE-mediated mRNA decay

SummaryTumor necrosis factor-α (TNF-α) is the most potent proinflammatory cytokine in mammals. The degradation of TNF-α mRNA is critical for restricting TNF-α synthesis and involves a constitutive decay element (CDE) in the 3′ 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-α mRNA and limits TNF-α 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.

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