Networks controlling mRNA decay in the immune system

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.

Upregulation of miR-142-3p in Peripheral Blood Mononuclear Cells of Operationally Tolerant Patients with a Renal Transplant

“…Such a process of regulation, already described for different miRNAs, 40 suggests that miRNAs act as key gene switches and as fine-tuning molecules, depending on the compartment and the specific biologic context. 20 Therefore, our data suggest that mir-142-3p is also implicated in the TGF-b pathway. However, because the modulation of one miRNA may affect multiple mRNAs that are also regulated by several other miRNAs, a direct link between these two molecules cannot be predicted at this stage.…”

“…16,17 Furthermore, the incomplete pattern of target recognition allows a single miRNA to target hundreds of mRNAs, and conversely, a single mRNA to be targeted by multiple miRNAs, thus affecting a broad range of gene networks. 18 Numerous studies have reported on the differential expression of miRNA in physiologic disorders or diseases, 19,20 and miRNA has been found to be modulated in biopsy specimens from kidney transplant recipients. [21][22][23] In this study, we investigated whether miRNA is modulated in the blood of patients with operational tolerance compared with a cohort of patients with stable graft function under classic immunosuppression.…”

MHC class I–associated peptides derive from selective regions of the human genome

“…Despite this regulatory potential, we initially remarked no difference in the lengths of 3′ UTRs (Figure 3). The density of AU-rich elements was similar; however, our analyses could not take into account the distinction between AU elements involved in rapid decay and finer stability regulation (46). Greater GC content was found in nonsource 3′ UTRs and along the entire mRNA transcript in general; this may reflect a positive association with mRNA levels in a degradation-independent manner (47).…”

A noncoding RNA produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease XRN1 and alters host mRNA stability

“…Based on models of the kinetics of mRNA accumulation (Elkon et al 2010), the alterations in mRNA half-lives that we observe during flavivirus infections are likely to have a much greater influence on the expression of naturally short-lived mRNAs as compared with longer-lived transcripts. Interestingly, many cytokines and factors involved in aspects of innate immunity are often encoded by short-lived transcripts (Schott and Stoecklin 2010). Thus flaviviruses may use this strategy to disturb the normal regulation of these factors and escape cellular surveillance mechanisms that would normally limit their replication and perhaps induce immunopathogenesis.…”