title: The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation.
abstract: TNF expression of macrophages is under stringent translational control that depends on the p38 MAPK/MK2 pathway and the AU-rich element (ARE) in the TNF mRNA. Here, we elucidate the molecular mechanism of phosphorylation-regulated translation of TNF. We demonstrate that translation of the TNF-precursor at the ER requires expression of the ARE-binding and -stabilizing factor human antigen R (HuR) together with either activity of the p38 MAPK/MK2 pathway or the absence of the ARE-binding and -destabilizing factor tristetraprolin (TTP). We show that phosphorylation of TTP by MK2 decreases its affinity to the ARE, inhibits its ability to replace HuR, and permits HuR-mediated initiation of translation of TNF mRNA. Since translation of TTP's own mRNA is also regulated by this mechanism, an intrinsic feedback control of the inflammatory response is ensured. The phosphorylation-regulated TTP/HuR exchange at target mRNAs provides a reversible switch between unstable/non-translatable and stable/efficiently translated mRNAs.
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tiedje
authors.forename: Natalia
authors.initials: N
authors.lastname: Ronkina
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tehrani
authors.forename: Sonam
authors.initials: S
authors.lastname: Dhamija
authors.forename: Kathrin
authors.initials: K
authors.lastname: Laass
authors.forename: Helmut
authors.initials: H
authors.lastname: Holtmann
authors.forename: Alexey
authors.initials: A
authors.lastname: Kotlyarov
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
mesh_terms: D063307:AU Rich Elements / Q000235:genetics*; D051959:ELAV Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D051959:ELAV Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011498:Protein Precursors; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C061153:tumor necrosis factor precursor