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.
- SourceAvailable from: Osamu Takeuchi
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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. "
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.Cell 05/2015; 161(5):1058-1073. DOI:10.1016/j.cell.2015.04.029 · 33.12 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) serve as the major innate immune sensors for detection of specific molecular patterns on various pathogens. TLRs activate signaling events mainly by utilizing ubiquitin-dependent mechanisms. Recent research advances have provided evidence that TLR signaling is linked to induction of autophagy. Autophagy is currently known to affect both of the immune defense and suppression of inflammatory responses. In TLR-associated immune responses, autophagic lysis of intracellular microbes (called xenophagy) contributes to the former mechanism, while the latter seems to be mediated by the control of the mitochondrial integrity or selective autophagic clearance of aggregated signaling proteins (called aggrephagy). Several autophagy-related ubiquitin-binding proteins, such as SQSTM1/p62 and NDP52, mediate xenophagy and aggrephagy. In this review, we summarize the expanded knowledge regarding TLR signaling and autophagy signaling. After that, we will focus on autophagy-associated signaling downstream of TLRs and the effect of autophagy on TLR signaling, thus highlighting the signaling crosstalk between the TLR-associated innate immune responses and the regulation of innate immunity by xenophagy and aggrephagy.Cellular Signalling 02/2012; 24(6):1150-62. DOI:10.1016/j.cellsig.2012.01.020 · 4.47 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) sense invading microbial pathogens and play crucial roles in the activation of innate and adaptive immunity. However, excessive TLR activation can disrupt immune homeostasis, and may be responsible for the development of autoimmune and inflammatory diseases. As such, the molecules and pathways that negatively control TLR signaling have been intensively investigated. Here, we discuss recent insights into the negative regulation of TLR signaling, with focus on three major mechanisms: (i) dissociation of adaptor complexes; (ii) degradation of signal proteins; and (iii) transcriptional regulation. We also highlight how pathogens negatively target TLR signaling as a strategy to evade the host immune response.Trends in Immunology 06/2012; 33(9):449-58. DOI:10.1016/j.it.2012.05.002 · 12.03 Impact Factor