RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway

Murakawa, Yuji; Hinz, Michael; Mothes, Janina; Schuetz, A.; Uhl, Michaël; Wyler, Emanuel; Yasuda, Tomoharu; Mastrobuoni, Guido; Friedel, Caroline C.; Dölken, Lars; Kempa, Stefan; Schmidt-Supprian, Marc; Blüthgen, Nils; Backofen, Rolf; Heinemann, Udo; Wolf, Jana; Scheidereit, Claus; Landthaler, Markus

doi:10.1038/ncomms8367

Cited by 97 publications

(143 citation statements)

References 58 publications

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“…A20 is an ubiquitin-editing enzyme that inhibits the NF-κB signalling pathway 55 . Roquin 1 uses its ROQ and CCCH zinc finger domains to contact a non-CDE-type stem–loop structure that is preceded by an ARE in the 3′ UTR of A20 mRNA and promotes its degradation 54 . These studies highlight the importance of post-transcriptional regulation of gene expression to control crucial cellular signal transduction pathways (FIG.…”

Section: Regulation Of Immune Cell Activationmentioning

confidence: 99%

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

2016

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Nearly 60 CCCH zinc finger proteins have been identified in humans and mice. These proteins are involved in the regulation of multiple steps of RNA metabolism, including mRNA splicing, polyadenylation, transportation, translation and decay. Several CCCH zinc finger proteins, such as tristetraprolin (TTP), roquin 1 and MCPIP1 (also known as regnase 1), are crucial for many aspects of immune regulation by targeting mRNAs for degradation and modulation of signalling pathways. In this Review, we focus on the emerging roles of CCCH zinc finger proteins in the regulation of immune responses through their effects on cytokine production, immune cell activation and immune homeostasis.

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Section: Regulation Of Immune Cell Activationmentioning

confidence: 99%

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

2016

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“…Recent reports link the modulation of single components of the IKK‐NF‐κB pathway at the RNA level by post‐transcriptional regulation (Glasmacher et al , ; Iwasaki et al , ; Murakawa et al , ). In this work, we reveal an NF‐κB‐independent function of the IKK complex in the global regulation of mRNA stability.…”

Section: Discussionmentioning

confidence: 99%

The IκB kinase complex is a regulator of mRNA stability

et al. 2018

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The IκB kinase (IKK) is considered to control gene expression primarily through activation of the transcription factor NF‐κB. However, we show here that IKK additionally regulates gene expression on post‐transcriptional level. IKK interacted with several mRNA‐binding proteins, including a Processing (P) body scaffold protein, termed enhancer of decapping 4 (EDC4). IKK bound to and phosphorylated EDC4 in a stimulus‐sensitive manner, leading to co‐recruitment of P body components, mRNA decapping proteins 1a and 2 (DCP1a and DCP2) and to an increase in P body numbers. Using RNA sequencing, we identified scores of transcripts whose stability was regulated via the IKK‐EDC4 axis. Strikingly, in the absence of stimulus, IKK‐EDC4 promoted destabilization of pro‐inflammatory cytokines and regulators of apoptosis. Our findings expand the reach of IKK beyond its canonical role as a regulator of transcription.

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“…23 Roquin localizes in P bodies and stress granules in cells and mainly targets translationally inactive mRNAs for degradation by recruiting the CCR4-NOT deadenylase complex. 18,31 In contrast, Regnase-1-mediated degradation of mRNAs in cells is independent from the CCR4-NOT deadenylase complex. 23 Regnase-1 binds to the ribosome, localizes in the endoplasmic reticulum and/or cytoplasm, and degrades translationally active mRNAs ( Figure 2).…”

Section: Molecular Mechanisms Of Regnase-1-mediated Mrna Decaymentioning

confidence: 99%

Endonuclease Regnase‐1/Monocyte chemotactic protein‐1‐induced protein‐1 (MCPIP1) in controlling immune responses and beyond

Takeuchi

2017

WIREs RNA

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The activation of inflammatory cells is controlled at transcriptional and posttranscriptional levels. Posttranscriptional regulation modifies mRNA stability and translation, allowing for elaborate control of proteins required for inflammation, such as proinflammatory cytokines, prostaglandin synthases, cell surface co-stimulatory molecules, and even transcriptional modifiers. Such regulation is important for coordinating the initiation and resolution of inflammation, and is mediated by a set of RNA-binding proteins (RBPs), including Regnase-1, Roquin, Tristetraprolin (TTP), and AU-rich elements/poly(U)-binding/degradation factor 1 (AUF1). Among these, Regnase-1, also known as Zc3h12a and Monocyte chemotactic protein-1-induced protein-1 (MCPIP1), acts as an endoribonuclease responsible for the degradation of mRNAs involved in inflammatory responses. Conversely, the RBPs Roquin and TTP trigger exonucleolytic degradation of mRNAs by recruiting the CCR4-NOT deadenylase complex. Regnase-1 specifically recognizes stem-loop structures present in 3 0 -untranslated regions of cytokine mRNAs, and directly degrades the mRNAs in a translation-and ATP-dependent RNA helicase upframeshift 1 (UPF1)-dependent manner that is reminiscent of nonsense-mediated decay. Regnase-1 regulates the activation of innate and acquired immune cells, and is critical for maintaining immune homeostasis as well as preventing over-activation of the immune system under inflammatory conditions. Furthermore, recent studies have revealed that Regnase-1 and its family members are involved not only in immunity but also in various biological processes. In this article, I review molecular mechanisms of Regnase-1-mediated mRNA decay and its physiological roles.

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RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway

Cited by 97 publications

References 58 publications

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

The IκB kinase complex is a regulator of mRNA stability

Endonuclease Regnase‐1/Monocyte chemotactic protein‐1‐induced protein‐1 (MCPIP1) in controlling immune responses and beyond

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