Abstract
Previous work by several laboratories has established that translation of picornavirus RNA requires active eIF2α for translation in cell free systems or after transfection in culture cells. Strikingly, we have found that encephalomyocarditis virus protein synthesis at late infection times is resistant to inhibitors that induce the phosphorylation of eIF2α whereas translation of encephalomyocarditis virus early during infection is blocked upon inactivation of eIF2α by phosphorylation induced by arsenite. The presence of this compound during the first hour of infection leads to a delay in the appearance of late protein synthesis in encephalomyocarditis virus-infected cells. Depletion of eIF2α also provokes a delay in the kinetics of encephalomyocarditis virus protein synthesis, whereas at late times the levels of viral translation are similar in control or eIF2α-depleted HeLa cells. Immunofluorescence analysis reveals that eIF2α, contrary to eIF4GI, does not colocalize with ribosomes or with encephalomyocarditis virus 3D polymerase. Taken together, these findings support the novel idea that eIF2 is not involved in the translation of encephalomyocarditis virus RNA during late infection. Moreover, other picornaviruses such as foot-and-mouth disease virus, mengovirus and poliovirus do not require active eIF2α when maximal viral translation is taking place. Therefore, translation of picornavirus RNA may exhibit a dual mechanism as regards the participation of eIF2. This factor would be necessary to translate the input genomic RNA, but after viral RNA replication, the mechanism of viral RNA translation switches to one independent of eIF2.
Highlights
The genome of picornaviruses comprises a molecule of singlestranded RNA of positive polarity that acts as the only viral mRNA that is translated in infected cells [1]
Upon binding of the virion to its receptor, the naked viral particles deliver the ssRNA molecule to the cytoplasm, where it is recognized and translated by the cellular protein synthesizing machinery [2]. This early viral translation is followed by RNA replication giving rise to large amounts of RNA molecules of positive polarity, some of which may serve as new mRNAs to direct the massive synthesis of viral proteins during the late phase of infection [3,4,5]
Our present results indicate that encephalomyocarditis virus (EMCV) protein synthesis does not require active eIF2 at late infection times, while this factor is necessary at early times, suggesting that EMCV mRNA translation can follow a dual mechanism for the synthesis of viral proteins
Summary
The genome of picornaviruses comprises a molecule of singlestranded RNA of positive polarity that acts as the only viral mRNA that is translated in infected cells [1]. Upon binding of the virion to its receptor, the naked viral particles deliver the ssRNA molecule to the cytoplasm, where it is recognized and translated by the cellular protein synthesizing machinery [2] This early viral translation is followed by RNA replication giving rise to large amounts of RNA molecules of positive polarity, some of which may serve as new mRNAs to direct the massive synthesis of viral proteins during the late phase of infection [3,4,5]. The structure and the eIF requirements for the translation of the different IRES-containing picornavirus RNAs may vary among the different species investigated Based on these differences, at present four classes of picornavirus IRESs can be considered [14], but all of them require eIF2 for efficient translation in cell free systems
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