Screening of posttranscriptional regulatory molecules of IκB-ζ.

Posttranscriptional regulatory elements in the 3′-untranslated region (UTR) of mRNAs play an important role in mRNA stabilization. Induction of IκB-ζ, a critical transcriptional regulator in the innate immune response, is mediated via specific mRNA stabilization by lipopolysaccharide (LPS) and interleukin (IL)-1β. It is known that the 3′-UTR of IκB-ζ, especially 165 nucleotides after the stop codon, plays a crucial role in mRNA stability. Herein, we show that AU-rich elements and miRNA targets in these 165 3′-UTR nucleotides are dispensable for stability of IκB-ζ mRNA. Additionally, NF-κB activation is important for IκB-ζ transcription, but dispensable for IκB-ζ mRNA stability. Interestingly, high-throughput screening results show that MyD88, a signal molecule responsive to LPS/IL-1β stimulation, is key for stabilizing IκB-ζ mRNA expression. Moreover, MyD88-deficient macrophages exhibited a decreased half-life of IκB-ζ mRNA expression. These results indicate that the LPS/IL-1β-MyD88 axis plays a crucial role for stabilization of IκB-ζ mRNA.