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

Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Nature Immunology (Impact Factor: 20). 12/2011; 12(12):1167-75. DOI: 10.1038/ni.2137
Source: PubMed


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.

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    • "Overexpression of Reg1 suppressed the luciferase activity in an RNase-activity dependent manner (Figure 1K). Consistent with a previous report (Iwasaki et al., 2011), overexpression of Reg1 suppressed Reg1 3′ UTR containing nucleotides 1-210, but not in the case where nucleotides 1-200, which contains the SL, were absent. Collectively, Reg1-bound mRNAs obtained by RIP-Seq are indeed targeted by Reg1 for degradation. "
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    ABSTRACT: Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Cell
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    • "This complex signals to translocate the transcription factors, IRF7 and NF-jB, from the cytoplasm to the nucleus for subsequent production of IFN and inflammatory cytokines. Given that MyD88 recruits several proteins , such as IRAK4, IRAK1, IRF7, to form a large complex [11], MVP may also bind those proteins in a MyD88-mediated complex . Further studies are needed to verify these putative interactions. "
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    Full-text · Article · Dec 2014 · Journal of Hepatology
    • "Activation of IL-1R or TLR led to phosphorylation of regnase-1 via the inhibitor of transcription factor NF-jB (IjB) kinase (IKK) complex, thus inducing a rapid ubiquitin–proteasome-mediated degradation of the protein. This regn- ase-1 degradation was important for high IL-6 mRNA expression, and re-expression of regnase-1 after four hours, which itself is a NF-jB target gene, inhibited sustained IL-6 expression [50]. Accordingly, Zc3h12a À/À mice show increased IL-6 production, and overexpressed regenase-1 interfered with the 3' UTR of the IL-6 mRNA and thereby accelerated IL-6 mRNA degradation [51]. "
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    ABSTRACT: Interleukin-6 (IL-6) is a multifunctional cytokine with well-defined pro- and anti-inflammatory properties. Although only small amounts in the picogram range can be detected in healthy humans, IL-6 expression is highly and transiently up-regulated in nearly all pathophysiological states. IL-6 induces intracellular signaling pathways after binding to its membrane-bound receptor (IL-6R), which is only expressed on hepatocytes and certain subpopulations of leukocytes (classic signaling). Transduction of the signal is mediated by the membrane-bound β-receptor glycoprotein 130 (gp130). In a second pathway, named trans-signaling, IL-6 binds to soluble forms of the IL-6R (sIL-6R), and this agonistic IL-6/sIL-6R complexes can in principle activate all cells due to the uniform expression of gp130. Importantly, several soluble forms of gp130 (sgp130) are found in the human blood, which are considered to be the natural inhibitors of IL-6 trans-signaling. Most pro-inflammatory roles of IL-6 have been attributed to the trans-signaling pathway, whereas anti-inflammatory and regenerative signaling, including the anti-bacterial acute phase response of the liver, is mediated by IL-6 classic signaling. In this simplistic view, only a minority of cell types expresses the IL-6R and is therefore responsive for IL-6 classic signaling, whereas gp130 is ubiquitously expressed throughout the human body. However, several reports point towards a much more complex situation. A plethora of factors, including proteases, cytokines, chemical drugs, and intracellular signaling pathways, are able to modulate the cellular expression of the membrane-bound and soluble forms of IL-6R and gp130. In this review, we summarize current knowledge of regulatory mechanisms that control and regulate the dynamic expression of IL-6 and its two receptors.
    No preview · Article · Jun 2014 · Cytokine
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