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.

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

“…IRESs, elements located in the leader region of a restricted class of mRNA, allow the initiation of mRNA translation independently on the Cap-structure [25,36,37]. The alternative mechanism of translation mediated by IRESs is important when the attenuation of global protein synthesis occurs in cells undergoing stress conditions, such as ER stress, hypoxia, UV irradiation, etc.…”

“…IRES-mediated Cap-independent translation is often supported by IRES trans-activating factors (ITAFs) [36]. In recent studies, it has been shown an increase of the SREBP-1a expression dependent on binding of hnRNP A1 on SREBP-1a 5 UTR [9,40].…”

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

“…Several cellular mRNAs were found to contain IRESs in their 5 UTR in addition to the 5 cap, implying that their translation can initiate through both cap-dependent and cap-independent mechanisms. In addition, different IRES elements interact with other trans-acting factors during initiation [81,82].…”

Relevance of Translation Initiation in Diffuse Glioma Biology and its Therapeutic Potential

“…Indeed, in the absence of cap-binding machinery or when cap-dependent initiation has been inhibited following cellular stress, alternative mechanisms can be initiated to ensure that proteins required for cell survival remain expressed. Several modes of translation have been proposed to explain cap-independent translation of mammalian mRNA with internal ribosomal entry site (IRES) being the most studied so far [17,18]. IRES-dependent initiation and current research in gliomas will be discussed hereafter.…”