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Networks controlling mRNA decay in the immune system

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Abstract The active control of mRNA degradation has emerged as a key regulatory mechanism required for proper gene expression in the immune system. An adenosine/uridine (AU)‐rich element (ARE) is at the heart of a first regulatory system that promotes the rapid degradation of a multitude of cytokine and chemokine mRNAs. AREs serve as binding sites for a number of regulatory proteins that either destabilize or stabilize the mRNA. Several kinase pathways regulate the activity of ARE‐binding proteins and thereby coordinate the expression of their target mRNAs. Small regulatory micro (mi)‐RNAs represent a second system that enhances the degradation of several mRNAs encoding important components of signal transduction cascades that are activated during adaptive and innate immune responses. Specific miRNAs are important for the differentiation of T helper cells, class switch recombination in B cells, and the maturation of dendritic cells. Excitement in this area of research is fueled by the discovery of novel RNA elements and regulatory proteins that exert control over specific mRNAs, as exemplified by an endonuclease that was found to directly cleave interleukin‐6 mRNA. Together, these systems make up an extensive regulatory network that controls decay rates of individual mRNAs in a precise manner and thereby orchestrates the dynamic expression of many factors essential for adaptive and innate immune responses. In this review, we provide an overview of relevant factors regulated at the level of mRNA stability, summarize RNA‐binding proteins and miRNAs that control their degradation rates, and discuss signaling pathways operating within this regulatory network Copyright © 2010 John Wiley & Sons, Ltd. 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 Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

Regulation of mRNA stability during innate immune responses. (a) Control of Toll‐like receptor (TLR) signaling by micro (mi)‐RNAs. The expression of miR‐9, miR‐146a, miR‐155, and let‐7e is induced upon macrophage stimulation, whereas miR‐125b is repressed. The mRNAs targeted by these miRNAs encode for essential components of the TLR signaling cascades, such as the TLR4 receptor; the serine‐threonine kinases RIP1, IRAK1, IRAK2, and IKKε; the ubiquitin ligase TRAF6; and the transcription factors IRF5 and NKκB. (b) Control of mRNA degradation via AU‐rich elements (AREs). Many mRNAs encoding cytokines and chemokines contain an ARE in their 3′UTR, which targets the mRNA for rapid degradation. ARE‐binding proteins (BPs), such as TTP, BRF1, KSRP, and AUF1 destabilize ARE‐mRNAs, whereas HuR and YB1 participate in stabilizing ARE‐mRNAs. Activation of p38‐MAPK, JNK, Akt, and PKCδ kinase pathways controls the activity of ARE‐BPs and causes stabilization of ARE‐mRNAs. (c) Schematic representation of the regulatory network that controls mRNA decay. The two major systems at work are miRNA‐mediated repression and ARE‐mediated mRNA decay. Additional mechanisms involve mRNA degradation induced by CUGBP1, endonucleolytic cleavage of mRNAs by MCPIP1, a constitutive decay element (CDE) in TNFα mRNA, and a stabilizing JNK‐response element (JRE) in IL‐2 mRNA.

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Regulation of mRNA stability in different immune cell types. (a) The RNA‐binding protein Roquin and miR‐101 suppress the expression of ICOS and neuropilin‐1 mRNA in naïve CD4+ T cells. ICOS and neuropilin‐1 are upregulated during differentiation into follicular T helper cells and mediate interactions with dendritic cells (DC). (b) Activation of the T cell receptor (TCR) induces the expression of miR‐155 in naïve CD4+ T cells. miR‐155 suppresses the c‐Maf transcription factor and the interferon (IFN)‐γ receptor subunit IFNGR1, and thereby contributes to the differentiation into type 1 T helper (Th1) cells. (c) In B cells, miR‐155 expression is induced upon stimulation with IL‐4 and LPS. miR‐155 enhances class switch recombination through suppression of the Pu.1 transcription factor and by enhancing phosphatidylinositol 3‐kinase (PI3K) signaling through the suppression of the phosphatidylinositol 5′‐phosphatase SHIP1. miR‐155 also inhibits the activation‐induced cytidine deaminase (AID) and thereby prevents aberrant chromosomal translocations. (d) Induction of miR‐155 expression upon activation of immature DCs causes downregulation of DC‐SIGN via inhibition of the Pu.1 transcription factor. This mechanism may contribute to the differentiation into mature DCs. DC‐SIGN is a lectin that binds mannose‐containing glycoproteins on the surface of pathogens and promotes phagocytosis in immature DCs.

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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Regulation of RNA Stability

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