IRES Trans-Acting Factors, Key Actors of the Stress Response

Abstract

The cellular stress response corresponds to the molecular changes that a cell undergoes in response to various environmental stimuli. It induces drastic changes in the regulation of gene expression at transcriptional and posttranscriptional levels. Actually, translation is strongly affected with a blockade of the classical cap-dependent mechanism, whereas alternative mechanisms are activated to support the translation of specific mRNAs. A major mechanism involved in stress-activated translation is the internal ribosome entry site (IRES)-driven initiation. IRESs, first discovered in viral mRNAs, are present in cellular mRNAs coding for master regulators of cell responses, whose expression must be tightly controlled. IRESs allow the translation of these mRNAs in response to different stresses, including DNA damage, amino-acid starvation, hypoxia or endoplasmic reticulum stress, as well as to physiological stimuli such as cell differentiation or synapse network formation. Most IRESs are regulated by IRES trans-acting factor (ITAFs), exerting their action by at least nine different mechanisms. This review presents the history of viral and cellular IRES discovery as well as an update of the reported ITAFs regulating cellular mRNA translation and of their different mechanisms of action. The impact of ITAFs on the coordinated expression of mRNA families and consequences in cell physiology and diseases are also highlighted.

Keywords: IRES; ITAF; chaperone; gene regulation; hnRNP; lncRNA; mRNA; nucleocytoplasmic translocation; ribosome; stress; stress granules; therapeutic targets; translation; translation initiation factor.

Figure 1

The regulation of the (lymph)angiogenic growth factor expression during hypoxia: (Lymph)angiogenic growth factors are regulated at the transcriptional and/or translational levels during hypoxia. In conditions of tumoral hypoxia, the regulation is both transcriptional and translational through the internal ribosome entry site (IRES)-dependent mechanism, whereas during cardiac ischemia in hypoxic cardiomyocytes, most regulation is translational [72]. The IRESs of (lymph)angiogenic growth factor mRNAs are activated during early hypoxia by an HIF1-independent mechanism.

Figure 2

The ITAFs use different mechanisms of action to control IRES-dependent translation. The different reported mechanisms of ITAFs to regulate IRES activities are schematized. For each mechanism, an example is shown with the names of the ITAF and of the IRES. The start point of translation is indicated by an arrow if translation initiation is increased or by a blocked arrow if translation initiation is inhibited. Each mechanism is detailed in the text.