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Post-transcriptional regulons coordinate the initiation and resolution of inflammation

Nature Reviews Immunology volume 10, pages 24–35 (2010)Cite this article

Subjects

Key Points

  • RNA-binding proteins that control mRNA stability and translation coordinately regulate the expression of proteins that initiate and resolve inflammation.

  • 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.

  • 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.

  • 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).

  • 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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Figure 1: Regulation of translation initiation.
Figure 2: Regulation of mRNA decay.
Figure 3: Modulators of the RNA-induced silencing complex.

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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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    Paul Anderson

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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

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

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

(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

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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