MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels.
We demonstrate that lipopolysaccharide-induced tumor necrosis factor (TNF) biosynthesis becomes independent of MAPKAP kinase 2 (MK2) when the AU-rich element (ARE) of the TNF gene is deleted. In spleen cells and macrophages where TNF biosynthesis is restored as a result of this deletion, interleukin (IL)-6 biosynthesis is still dependent on MK2. In MK2-deficient macrophages the half-life of IL-6 mRNA is reduced more than 10-fold, whereas the half-life of TNF mRNA is only weakly decreased. It is shown that the stability of a reporter mRNA carrying the AU-rich 3'-untranslated region (3'-UTR) of IL-6 is increased by MK2. The data provide in vivo evidence that the AU-rich 3'-UTRs of TNF and IL-6 are downstream to MK2 signaling and make MK2 an essential component of mechanisms that regulate biosynthesis of IL-6 at the levels of mRNA stability, and of TNF mainly through TNF-ARE-dependent translational control.
Neininger
Armin
A
Innovationskolleg Zellspezialisierung, Martin-Luther-Universität Halle/Wittenberg, 06120 Halle, Germany.
Kontoyiannis
Dimitris
D
Kotlyarov
Alexey
A
Winzen
Reinhard
R
Eckert
Rolf
R
Volk
Hans-Dieter
HD
Holtmann
Helmut
H
Kollias
George
G
Gaestel
Matthias
M
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D015850:Interleukin-6 / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D017384:Sequence Deletion; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D000099190:MAP-Kinase-Activated Kinase 2
D020413:3' Untranslated Regions; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2; C000630987:Hnrpd protein, mouse