title: Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs.
abstract: Tumor 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.
authors.affiliation: Helmholtz Junior Research Group Posttranscriptional Control of Gene Expression, German Cancer Research Center, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Leppek
authors.forename: Johanna
authors.initials: J
authors.lastname: Schott
authors.forename: Sonja
authors.initials: S
authors.lastname: Reitter
authors.forename: Fabian
authors.initials: F
authors.lastname: Poetz
authors.forename: Ming C
authors.initials: MC
authors.lastname: Hammond
authors.forename: Georg
authors.initials: G
authors.lastname: Stoecklin
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D059372:Nucleotide Motifs; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry; D012097:Repressor Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D012333:RNA, Messenger; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; C582114:roquin-2 protein, mouse; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases