The Magic Bullet Of The GPX5

It has been proposed that unlike in the case of the TMEV IRES, PTBP1 alone is unable to promote the RNA structural modifications to the FMDV IRES necessary for ribosome association and Vorinostat mouse translation initiation. This is likely due to differences in the nucleotide sequence within these Type II IRES structures and associated differences in the way in which PTBP1 binds and arranges these regions, forcing FMDV to rely on PA2G4 to shape a functionally competent IRES structure (Pilipenko et al., 2000). PA2G4 was also shown to interact with TMEV and EMCV RNA, so this protein likely binds RNA non-specifically. However, EMCV IRES-driven translation has been shown to be unaffected by the presence of PA2G4, and PA2G4 does not interact with PTBP1, corroborating the fact that translation initiation from the EMCV IRES is independent of PA2G4 (Monie et al., 2007). Interestingly, despite the fact that FMDV and EMCV have different ITAF requirements, experiments comparing the sites of hydroxyl radical cleavage within the IRES structures from the eIF4G hub demonstrated that when these Type II IRESs interact with their cognate ITAFs, similar structural conformations are adopted (Yu et al., 2011). This suggests that although these IRES sequences can vary by ~50%, their shared requirement for PTBP1 seems to lie in the fact that it acts as versatile adaptor protein, whether alone or in combination with other ITAFs, in translation initiation form Type II IRESs. Minimal vs. stimulatory ITAFs It is important to note that while there has been rather extensive study of the Type I and Type II IRESs and their associated ITAFs, there is some variability in the reported ITAF requirements across particular viral species. For the Type I IRES elements tested (poliovirus, HRV 2, and CVB3), PTBP1 has been shown to be both required or unnecessary (Hunt and Jackson, 1999; Verma et al., 2010; Sweeney et al., 2014). Similarly, for viruses containing Type II IRES elements, there is discrepancy in the obligatory ITAFs reported. PTBP1 is required for FMDV translation, but the requirement for this ITAF in EMCV translation appears conditional upon the reporter and IRES variant utilized in experiments (Kaminski and Jackson, 1998). Additionally, translation from the TMEV IRES has been shown to be independent of, as well as strongly dependent on, PTBP1 (Kaminski et al., 1995; Pilipenko et al., 2001). As mentioned previously, the inconsistencies in reported ITAFs is likely a result of the assay used (in vitro compared to experiments in cells) as well as the use of different strains of virus/sequences of reporter constructs. These apparently different results likely point to the fact that there are some minimal ITAFs required for Type I and Type II IRES elements but a multitude of ITAFs that play some stimulatory or translation-enhancing role depending on the specific context of an infection.