title: Tristetraprolin-driven regulatory circuit controls quality and timing of mRNA decay in inflammation.
abstract: For a successful yet controlled immune response, cells need to specifically destabilize inflammatory mRNAs but prevent premature removal of those still used. The regulatory circuits controlling quality and timing in the global inflammatory mRNA decay are not understood. Here, we show that the mRNA-destabilizing function of the AU-rich element-binding protein tristetraprolin (TTP) is inversely regulated by the p38 MAPK activity profile such that after inflammatory stimulus the TTP-dependent decay is initially limited to few mRNAs. With time, the TTP-dependent decay gradually spreads resulting in cumulative elimination of one third of inflammation-induced unstable mRNAs in macrophages in vitro. We confirmed this sequential decay model in vivo since LPS-treated mice with myeloid TTP ablation exhibited similar cytokine dysregulation profile as macrophages. The mice were hypersensitive to LPS but otherwise healthy with no signs of hyperinflammation seen in conventional TTP knockout mice demonstrating the requirement for myeloid TTP in re-installment but not maintenance of immune homeostasis. These findings reveal a TTP- and p38 MAPK-dominated regulatory mechanism that is vital for balancing acute inflammation by a temporally and qualitatively controlled mRNA decay.
authors.affiliation: Max F. Perutz Laboratories, Center for Molecular Biology, University of Vienna, Vienna, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Kratochvill
authors.forename: Christian
authors.initials: C
authors.lastname: Machacek
authors.forename: Claus
authors.initials: C
authors.lastname: Vogl
authors.forename: Florian
authors.initials: F
authors.lastname: Ebner
authors.forename: Vitaly
authors.initials: V
authors.lastname: Sedlyarov
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Gruber
authors.forename: Harald
authors.initials: H
authors.lastname: Hartweger
authors.forename: Raimund
authors.initials: R
authors.lastname: Vielnascher
authors.forename: Marina
authors.initials: M
authors.lastname: Karaghiosoff
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Ivo
authors.initials: I
authors.lastname: Hofacker
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Pavel
authors.initials: P
authors.lastname: Kovarik
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020871:RNA Stability / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D051816:Tristetraprolin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051816:Tristetraprolin; D048051:p38 Mitogen-Activated Protein Kinases