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.