Key Points
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RNA-binding proteins that control mRNA stability and translation coordinately regulate the expression of proteins that initiate and resolve inflammation.
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The interferon-γ-activated inhibitor of translation (GAIT) system ensures that inflammatory mediators such as ceruloplasmin, chemokines and chemokine receptors are expressed in a regulated pulse. Transcripts encoding these proteins contain a 29-nucleotide hairpin in their 3′ untranslated regions (the GAIT element) that recruits a multisubunit complex (the GAIT complex) that inhibits translation initiation.
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Steroid receptor co-activator 3 (SRC3) is a transcriptional co-activator that also functions as a translational co-repressor. SRC3 binds to the translational repressor T cell intracellular antigen 1 (TIA1) and increases its affinity for a regulatory element found in the 3′ untranslated region of tumour necrosis factor transcripts. By this mechanism, SRC3 promotes the initiation and resolution of inflammation.
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Tristetraprolin (TTP) is a zinc-finger protein that binds adenine- and uridine-rich regulatory elements found in the 3′ untranslated regions of mRNAs encoding both pro- and anti-inflammatory proteins. By promoting the degradation of these transcripts, TTP helps define the nature of the inflammatory response (for example, intense and short-lived versus mild and prolonged).
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RNA-binding proteins that target adenine- and uridine-rich regulatory elements in the 3′ untranslated regions of transcripts encoding pro- and anti-inflammatory mediators can interact with microRNA-containing RNA-induced silencing complexes to modulate mRNA stability and translation. Examples include TTP–microRNA (miR)-16, fragile X mental retardation syndrome-related 1–miR-369-3 and HuR–let-7.
Abstract
Transcriptional control mechanisms chart the course of the inflammatory response by synthesizing mRNAs encoding proteins that promote or inhibit inflammation. Because these mRNAs can be long-lived, turning off their synthesis does not rapidly stop or change the direction of inflammation. Post-transcriptional mechanisms that modify mRNA stability and/or translation provide more rapid and flexible control of this process and are particularly important in coordinating the initiation and resolution of inflammation. Here, I review the surprising variety of post-transcriptional control mechanisms that regulate the initiation and resolution of inflammation and discuss how these mechanisms are integrated to coordinate this essential process.
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Acknowledgements
I thank V. Salinas for help in researching and drafting the section on post-transcriptional control by zinc-finger proteins. I thank N. Kedersha for critical review of the manuscript. This work was supported by grants from the US National Institutes of Health and the American College of Rheumatology.
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Glossary
- Transcriptional regulon
-
The set of genes that are transcribed when a transcription factor is activated. Often these genes are involved in a common functional programme and their expression is coordinately turned on and off.
- Post-transcriptional regulon
-
The set of mRNAs that are targeted by a post-transcriptional control protein that coordinately regulates factors governing mRNA processing such as stability and/or translation. Often these mRNAs encode proteins involved in a common functional programme. Given that each mRNA is present in multiple copies in a cell, these regulons have the potential to coordinate overlapping functions temporally at different locations within the cell.
- 3′ untranslated region
-
(3′ UTR). The mRNA sequence extending from the stop codon to the poly(A) tail.
- Initiation phase
-
The part of the inflammatory response in which pro-inflammatory proteins and lipids are synthesized.
- Resolution phase
-
The part of the inflammatory response in which the expression of pro-inflammatory proteins and lipids is turned off and anti-inflammatory proteins and lipids actively reverse the inflammatory process.
- Adenine- and uridine-rich element
-
(ARE). An RNA domain found in the 3′ UTR of many RNAs that promotes silencing or decay.
- MicroRNA
-
(miRNA). A single-stranded RNA, ∼23 nucleotides in length, that is derived from hairpin-containing transcripts and binds to argonaute proteins as part of the RNA-induced silencing complex.
- tRNA multisynthetase complex
-
(MSC). A high molecular weight complex composed of several aminoacyl tRNA synthetases and other proteins.
- Cytosine- and adenine-rich instability element
-
(CARE). A motif that is found in the 3′ UTR of transcripts, including those of CD154, that recruits HNRNPL to repress translation initiation.
- Cytosine- and uridine-rich instability element
-
(CURE). A motif that is found in the 3′ UTR of transcripts, including those of CD154, that recruits the polypyrimidine tract binding protein to regulate mRNA stability.
- Luciferase reporter transcript
-
An mRNA with an open reading frame encoding luciferase, a fluorescent protein (the expression of which is easily quantifiable), and a 3′ UTR, which contains regulatory elements that control mRNA stability and translation.
- Capped mRNA
-
A transcript that begins with a 7-methyl-guanosine residue at the 5′ end.
- tRNAimet
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The initiator tRNA with an amino acyl link to methionine. This is a special tRNA that is required to initiate translation. It is found in a ternary complex with eIF2 and GTP.
- eIF2α
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A regulatory subunit of the eukaryotic translation initiation factor 2 complex that is part of a larger ternary complex (eIF2–GTP–tRNAimet) that positions the initiator methionine at the AUG initiation codon of an mRNA and enables ribosome joining to commence protein translation. Phosphorylation of eIF2α by stress-activated kinases decreases the availability of the ternary complex and inhibits protein translation.
- Argonaute protein
-
A member of a family of proteins associated with microRNAs, containing both a PIWI (P-element induced wimpy testis) domain and a PAX (PIWI Argonaute Zwille) domain. A subset of argonaute proteins have endonuclease activity and cleave mRNAs, whereas others only silence translation.
- Differentiation control element
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(DICE). A cytosine- and uridine-rich sequence found in the 3′ UTR of 15-lipoxygenase transcripts that recruits hnRNPE1 and hnRNPK to repress translation initiation.
- RNA-induced silencing complex
-
(RISC). A ribonucleoprotein complex, composed of argonaute proteins bound to miRNAs, that promotes mRNA decay and translational repression of target transcripts.
- Seed region
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Nucleotides 2–7 from the 5′ end of miRNAs that interact with complementary sequences in the 3′ untranslated region of target mRNAs.
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Anderson, P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nat Rev Immunol 10, 24–35 (2010). https://doi.org/10.1038/nri2685
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DOI: https://doi.org/10.1038/nri2685
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