title: Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms.
abstract: Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.
authors.affiliation: Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; CREST, JST, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Mino
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, 13125 Berlin, Germany.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Murakawa
authors.affiliation: Laboratory of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fukao
authors.affiliation: Laboratory of Systems Immunology, Osaka University, Suita, Osaka 565-0871, Japan; Immuno-genomics Research Unit, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Alexis
authors.initials: A
authors.lastname: Vandenbon
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, 13125 Berlin, Germany.
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Wessels
authors.affiliation: Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; CREST, JST, Kyoto 606-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ori
authors.affiliation: Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Uehata
authors.affiliation: Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; CREST, JST, Kyoto 606-8507, Japan.
authors.forename: Sarang
authors.initials: S
authors.lastname: Tartey
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, 13125 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ohler
authors.affiliation: Laboratory of Systems Immunology, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Integrated Biological Information, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, 13125 Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Landthaler
authors.affiliation: Laboratory of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; CREST, JST, Kyoto 606-8507, Japan. Electronic address: otake@virus.kyoto-u.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D001483:Base Sequence; D018388:Codon, Terminator; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009690:Nucleic Acid Conformation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018388:Codon, Terminator; D012333:RNA, Messenger; C484446:Rent1 protein, mouse; D012269:Ribosomal Proteins; D015534:Trans-Activators; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse