Abstract
Poliovirus RNA utilizes eIF2 for the initiation of translation in cell free systems. Remarkably, we now describe that poliovirus translation takes place at late times of infection when eIF2 is inactivated by phosphorylation. By contrast, translation directed by poliovirus RNA is blocked when eIF2 is inactivated at earlier times. Thus, poliovirus RNA translation exhibits a dual mechanism for the initiation of protein synthesis as regards to the requirement for eIF2. Analysis of individual poliovirus non-structural proteins indicates that the presence of 2Apro alone is sufficient to provide eIF2 independence for IRES-driven translation. This effect is not observed with a 2Apro variant unable to cleave eIF4G. The level of 2Apro synthesized in culture cells is crucial for obtaining eIF2 independence. Expression of the N-or C-terminus fragments of eIF4G did not stimulate IRES-driven translation, nor provide eIF2 independence, consistent with the idea that the presence of 2Apro at high concentrations is necessary. The finding that 2Apro provides eIF2-independent translation opens a new and unsuspected area of research in the field of picornavirus protein synthesis.
Highlights
Viral proteases play an important part both in the generation of mature viral proteins and in the modulation of cellular functions [1,2]
This is the case of Sindbis virus 26S mRNA, which does not require intact eIF4G [32] or active eIF2 [33] for translation in the infected cells, whereas these eIFs are necessary to initiate protein synthesis on this viral mRNA in cell-free systems [31]
It is generally accepted that picornavirus RNA needs eIF2 to initiate translation, there is some evidence that this factor can be phosphorylated at late times of infection [26,34]
Summary
Viral proteases play an important part both in the generation of mature viral proteins and in the modulation of cellular functions [1,2]. It seems reasonable to think that the main purpose of PV 2Apro and FMDV Lpro is to modify cellular functions Both proteases bisect eIF4G at a position close to each other. Hydrolysis of eIF4G by PV 2Apro inhibits the canonical mechanism of translation, which is cap-dependent and promotes a noncanonical mechanism in which eIF4E and cap recognition are not necessary [4]. Apart from this cleavage, PV 2Apro can hydrolyze other cellular proteins, the exact degradome for this protease has still not been defined. PV 2Apro blocks cap-dependent translation upon eIF4G cleavage and interferes with mRNA export to the cytoplasm; both events abolish cellular gene expression and abrogate cellular responses to viral infection
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