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

Abstract

The cellular stress response corresponds to the molecular changes that cell undergoes in response to various environmental stimuli. It induces drastic changes in the regulation of gene expression, at transcriptional and post-transcriptional levels. Actually, translation is strongly affected with a blockade of the classical cap-dependent mechanism, whereas alternative mechanisms are activated to support translation of specific mRNAs. One of the major mechanisms 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 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. Importantly, cellular mRNA IRESs are regulated by IRES trans-acting factor (ITAFs), exerting their action by at least nine different mechanisms. This review presents an update of the reported ITAFs regulating cellular mRNA translation and of the different mechanisms allowing them to control translation initiation in specific conditions. The impact of ITAFs on coordinated expression of mRNA families and consequences in cell physiology and diseases are also highlighted.

Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia

“…HuR may bind to an AU-rich element present in the 3' untranslated region of the VASH1 mRNA. However, in other studies, HuR has also been described as an ITAF, thus it is possible that VASH1 itself may be induced by an IRES-dependent mechanism (10,33,34). The anti-angiogenic function of VASH1 may appear inconsistent with its ability to activate the IRES of an angiogenic factor.…”

“…4). VASH1 has been observed in both the nucleus and the cytoplasm, and no striking nucleocytoplasmic relocalization is visible in response to hypoxia, in contrast to other ITAFs such as hnRNPA1 or nucleolin which shuttle to cytoplasm upon stress (10,13,15,38,39). Interestingly, VASH1, appears as foci whose size increases in hypoxia, suggesting that it could be partly translocated to stress granules.…”

“…One of the major alternative mechanisms able to overcome this global inhibition of translation by stress depends on internal ribosome entry sites (IRESs) that correspond to RNA structural elements allowing the direct recruitment of the ribosome on mRNA. As regards the molecular mechanisms of IRES activation by stress, several studies have reported the involvement of RNA binding proteins, called IRES trans-acting factors (ITAFs), able to stabilize the adequate RNA conformation allowing ribosome recruitment (9)(10)(11)(12)(13). Interestingly, subcellular relocalization of ITAFs plays a critical role in IRES-dependent translation (14).…”

“…Interestingly, subcellular relocalization of ITAFs plays a critical role in IRES-dependent translation (14). Indeed, many RNA-binding proteins are known to shuttle between nucleus and cytoplasm, and it has been reported that cytoplasmic relocalization of ITAFs such as PTB, PCBP1, RBM4 or nucleolin is critical to activate IRESdependent translation (10,13,14). In contrast, other ITAFs such as hnRNPA1, may have a negative impact on IRES activity when accumulating in the cytoplasm (15).…”

“…However, how ITAFs participate in the regulation of the hypoxic response remains a challenging question to address. IRESs are present in the mRNAs of several (lymph)angiogenic growth factors in the FGF and VEGF families, suggesting that the IRES-dependent mechanism might be a major way to activate angiogenesis and lymphangiogenesis during stress (2,10,13,(16)(17)(18)(19). However, most studies of the role of hypoxia in gene expression regulation have been performed in tumoral hypoxia, while it has been reported that tumoral angiogenesis leads to formation of abnormal vessels that are non functional, which strongly differs from non tumoral angiogenesis that induces formation of functional vessels (20).…”