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Expression of the cellular inhibitor of apoptosis protein 1 (cIAP1) is unexpectedly repressed at the level of translation under normal physiological conditions in many cell lines. We have previously shown that the 5' untranslated region of cIAP1 mRNA contains a stress-inducible internal ribosome entry site (IRES) that governs expression of cIAP1 protein. Although inactive in unstressed cells, the IRES supports cap-independent translation of cIAP1 in response to endoplasmic reticulum stress. To gain an insight into the mechanism of cIAP1 IRES function, we empirically derived the minimal free energy secondary structure of the cIAP1 IRES using enzymatic cleavage mapping. We subsequently used RNA affinity chromatography to identify several cellular proteins, including nuclear factor 45 (NF45) as cIAP1 IRES binding proteins. In this report we show that NF45 is a novel RNA binding protein that enhances IRES-dependent translation of endogenous cIAP1. Further, we show that NF45 is required for IRES-mediated induction of cIAP1 protein during the unfolded protein response. The data presented are consistent with a model in which translation of cIAP1 is governed, at least in part, by NF45, a novel cellular IRES trans-acting factor., Competing Interests: The authors declare no conflict of interest.

Expression of the proteome is tightly regulated at the level of protein synthesis. Translational control is a critical homeostatic mechanism that allows the cell to rapidly change its phenotype in the face of an intra- and extra-cellular environment in constant flux. It is becoming increasingly clear that when it comes to protein translation during cell stress, all mRNAs are not treated equally. The translation of the majority of mRNAs is compromised during cell stresses that induce programmed cell death such as hypoxia, or DNA damage. However, cellular messages harbouring Internal Ribosome Entry Site elements (IRES) within their 5' untranslated regions are insensitive to stress-induced repression of global translation. Instead, these IRES-containing mRNAs use a poorly understood alternative mechanism of translation that allows continued expression of proteins that are required for the cell to recover from a transient stress or to proceed down the path toward apoptotic death. This review will highlight recent literature that suggests why global translation rates are impaired during stress and apoptosis and how these conditions mediate a switch in the mechanism by which pertinent proteins are synthesized. In addition, recent advances towards our understanding of the physiological role and mechanism of IRES-mediated translation in the context of cell stress-induced apoptosis and human disease will be examined.