title: IL-1-induced post-transcriptional mechanisms target overlapping translational silencing and destabilizing elements in IκBζ mRNA.
abstract: The inflammatory cytokine IL-1 induces profound changes in gene expression. This is contributed in part by activating translation of a distinct set of mRNAs, including IκBζ, as indicated by genome-wide analysis of changes in ribosomal occupancy in IL-1α-treated HeLa cells. Polysome profiling of IκBζ mRNA and reporter mRNAs carrying its 3' UTR indicated poor translation in unstimulated cells. 3' UTR-mediated translational silencing was confirmed by suppression of luciferase activity. Translational silencing was unaffected by replacing the poly(A) tail with a histone stem-loop, but lost under conditions of cap-independent internal initiation. IL-1 treatment of the cells caused profound shifts of endogenous and reporter mRNAs to polysome fractions and relieved suppression of luciferase activity. IL-1 also inhibited rapid mRNA degradation. Both translational activation and mRNA stabilization involved IRAK1 and -2 but occurred independently of the p38 MAPK pathway, which is known to target certain other post-transcriptional mechanisms. The translational silencing RNA element contains the destabilizing element but requires additional 5' sequences and is impaired by mutations that leave destabilization unaffected. These differences in function are associated with differential changes in protein binding in vitro. Thus, rapid degradation occurs independently of the translational silencing effect. The results provide evidence for a novel mode of post-transcriptional control by IL-1, which impinges on the time course and pattern of IL-1-induced gene expression.
authors.affiliation: Institute of Biochemistry, Medical School Hannover, D-30623 Hannover, Germany.
authors.forename: Sonam
authors.initials: S
authors.lastname: Dhamija
authors.forename: Anneke
authors.initials: A
authors.lastname: Doerrie
authors.forename: Reinhard
authors.initials: R
authors.lastname: Winzen
authors.forename: Oliver
authors.initials: O
authors.lastname: Dittrich-Breiholz
authors.forename: Azadeh
authors.initials: A
authors.lastname: Taghipour
authors.forename: Nancy
authors.initials: N
authors.lastname: Kuehne
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
authors.forename: Helmut
authors.initials: H
authors.lastname: Holtmann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; D007375:Interleukin-1; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger