The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR–IL-1R by controlling degradation of regnase-1

Abstract

Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.

Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo

“…It has been recently shown that levels of Regnase-1 expression are regulated through TLR signaling, in which Regnase-1 is induced in peritoneal macrophages after LPS treatment (8,9). Interestingly, levels of Arid5a protein were also controlled through TLR signaling.…”

“…For example, TTP phosphorylation by MK2 downstream of p38 MAPK signaling facilitates TTP to degrade mRNA through inhibition of deadenylase (28). Regnase-1 is phosphorylated by the IκB kinase (IKK) complex downstream of myeloid differentiation primary response protein 88 (Myd88) signaling, which undergoes ubiquitination and degradation (8). Accordingly, it is possible that the binding activity of Arid5a is also regulated by specific protein kinases, including p38 MAPK and IKK complex.…”

“…AUF1 has been shown to recognize mRNA stem-loop structures and AREs through its RNA recognition motif (RRM), although the mechanism of destabilization of IL-6 mRNA by AUF1 remains to be resolved (22). More recently, it has been reported that Regnase-1 is able to degrade IL-6 mRNA by recognizing the stem-loop region (its predicted site 84-103 in the IL-6 3′ UTR) via its CCCH zinc finger domain (8,9,25). In contrast, the role of RNA binding proteins in stabilization of IL-6 mRNA is not clearly understood.…”

“…The molecular mechanisms involved in transcriptional control of IL-6 expression have been extensively studied, and important roles for the transcription factors nuclear factor-kappa B (NF-κB) and CCAAT enhancer binding protein β (C/EBPβ), also known as NF-IL6, have been demonstrated (6,7). However, almost nothing is known about posttranscriptional regulatory mechanisms that specifically target IL-6 mRNA, except for the identification of zinc finger CCCH-type containing protein 12A (Zc3h12a), which is also called Regnase-1 (8), an ribonuclease (RNase) controlling immune responses by selectively regulating IL-6 mRNA decay (9).…”

Implications of IL-6 Targeting Therapy for Sepsis

“…Recently, our group and the Akira group clarified the post-transcriptional regulatory mechanisms of IL-6 mRNA by two counteractive molecules [11,12]. Akira et al found that Regnase-1, a kind of nuclease, which binds at the site 3'-untranslated region (3'-UTR) and destabilizes of IL-6 mRNA.…”