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The resultant IFN mRNA is exported to the cytoplasm where it is translated and then secreted, inducing a secondary response in an autocrine and [http://www.selleckchem.com/products/SB-203580.html SB203580 cell line] paracrine process. This results in the activation of a second signaling cascade involving many effectors and transcription factors such as signal transducer and activator of transcription (STAT) proteins, which translocate to the nucleus. Within the nucleus, these proteins activate  transcription of additional ISGs. These IFN stimulated gene products target the pathogen for destruction (Younessi et al., 2012). Changes made to the NPC by picornaviruses can lead to an attenuation in ISG expression and the associated antiviral response. Nup 98 is cleaved much more rapidly than the other Nup targets in poliovirus infected cells, and this has been suggested to be an early  target of picornavirus proteins to diminish the transcriptional-induction of antiviral genes. Experiments utilizing guanidine hydrochloride, which inhibits enterovirus RNA replication and, as a result, normal levels of viral protein production, have shown that cleavage of Nup 98 in poliovirus-infected cells is not sufficient to cause relocalization of proteins like nucleolin and that high concentrations of viral proteins are needed to degrade other nucleoporin targets to allow the widespread redistribution of nuclear-resident proteins to the cytoplasm (Park et al., 2008). Nup 98 is a component of the NPC but can also be found dissociated from this complex both in the nucleus and the cytoplasm. Enteroviral 2A and cardioviral L may be capable of targeting free Nup 98 prior  to direct transcriptional shut-off, which occurs when 3C precursors enter the nucleus of infected cells (discussed in the subsequent section), and interfere with signaling to the nucleus and/or the export of ISG transcripts. As a result, the virus may be able to avoid inducing an early antiviral response within the cell and promote maximal viral amplification (Park et al., 2008). Interestingly, Nup 98 has recently been shown to act as a transcription factor and induce the expression of antiviral defense genes in Drosophila (Panda et al., 2014). Therefore, the rapid degradation of Nup 98 in infected cells could allow enteroviruses to limit innate antiviral responses as well as set the stage for dysregulation of nucleocytoplasmic trafficking early during infection. The importance of restricting the production of IFN-��/�� during picornavirus infection is demonstrated by the fact that pre-treatment of cells with IFN-��/�� inhibits picornavirus replication, confirming that once ISG products are expressed they cannot be overcome (Chinsangaram et al., 2001). As mentioned above, the cardioviral TMEV L protein prevents export of cellular mRNAs from the nucleus.