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

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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′‐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. WIREs RNA 2018, 9:e1449. doi: 10.1002/wrna.1449 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease
Schematic representations of potential stem‐loop binding proteins, Roquin and Regnase‐1 and Zc3h12 family members. Regnase‐1 and Zc3h12 family proteins comprise a PilT N‐terminal‐like RNase domain followed by a CCCH‐type zinc finger domain. The Zc3h12 family also harbors an N‐terminal domain similar to ubiquitin‐associating protein and a C‐terminal helical domain. In addition, Regnase‐1 has a DSGxxS motif phosphorylated by the IκB kinase complex. Roquin‐1 harbors an N‐terminal RING finger domain, followed by an RNA‐binding ROQ domain and a CCCH‐type zinc finger domain, a proline‐rich domain and a coiled‐coil domain.
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Modification of RNA‐binding proteins in response to inflammatory stimuli. (a) Toll‐like receptor (TLR) signaling activates MAP kinases and IκB kinase (IKK) in innate immune cells. p38 MAP kinase activation leads to MK2‐mediated phosphorylation of Tristetraprolin (TTP), which sequester TTP from the target mRNAs by binding with 14‐3‐3 protein. IKK phosphorylates Regnase‐1, leading to stabilization of Il6 mRNAs by degrading Regnase‐1. (b) T‐cell receptor signaling activates MALT1 protease, cleaving Regnase‐1 and Roquin protein. Decreased expression of Regnase‐1 and Roquin stabilizes c‐Rel, Icos, and Ox40 mRNAs, thereby facilitating T‐cell activation.
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Spatiotemporal regulation of inflammatory mRNAs by Regnase‐1 and Roquin. A set of Toll‐like receptor (TLR)‐inducible inflammatory mRNAs harbor common stem‐loop structures recognized by Regnase‐1 and Roquin. Whereas Regnase‐1 localized in the endoplasmic reticulum (ER) binds with ribosomes and degrades its target mRNAs in a translation‐dependent fashion, Roquin is present in P bodies and stress granules, and degrades translationally inactive mRNAs by interacting with the CCR4‐NOT deadenylase complex. Regnase‐1 associates ATP‐dependent RNA helicase upframeshift 1 (UPF1) following translation termination, and UPF1 remodels an unknown messenger ribonucleoprotein, enabling Regnase‐1 to degrade its target mRNAs. Regnase‐1 and Roquin contribute to the control of inflammatory mRNA degradation in acute and late phases of inflammation, respectively.
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA in Disease and Development > RNA in Disease

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