That Target the Nuclear Pore. As mentioned above, HRV also induces cleavage of Nup62, Nup153 and most probably Nup98, leading to the impairment of nuclear protein import [159] . Nevertheless, PV and HRV 2A pro exhibit high homology and both proteases are therefore expected to share common targets. In contrast, the 2A gene of cardioviruses encodes a short peptide with autoproteolytic activity but lacks trans-protease activity. However, EMCV and mengovirus are able to damage NPC [202] . As occurs in PV-infected cells, these cardioviruses induce both protein nuclear import inhibition and late membrane leakiness but they do not induce the cleavage of Nups [160, 202, 203] . Cardioviruses encode an additional protein known as L protein, which is highly cytopathic although it lacks protease activity (in contrast to aphthovirus L pro ). L protein contains a Zinc finger domain, and an acidic region, which is proposed to be phosphorylated in infected cells [204] . Individual expression of this protein in cultured cells or in cell-free systems induces several cellular disorders including the inhibition of protein nuclear import that resembles that observed in EMCV-infected cells [160, 203] . Several studies reported EMCV L protein mutations that resulted in defective virus growth phenotypes in cell culture [202, 204] . In particular, mutations in the zinc finger domain (Cys19Ala and Cys22Ala) or in the acidic region (Thr47Ala) partially avoid blockade of protein trafficking between the nucleus and the cytoplasm [202] . Taken together, these data support the involvement of cardiovirus L protein in NPC damaging and in the inhibition of protein nuclear import, inducing Nups phosphorylation rather than their cleavage. Indeed, Nup62 is quickly and strongly phosphorylated after EMCV infection (2 hpi), and it was clearly detected by conventional Western blotting. Nevertheless, analysis with Pro-Q diamond phosphoprotein stain revealed that Nup153 and Nup214 are also phosphorylated to a certain extent upon EMCV infection. Notably, Nups phosphorylation was avoided when Cys19Ala mutation was inserted in the L protein sequence, suggesting that the Zinc finger domain is essential for this posttranslational modification to occur [160] . However, the exact role of Nups phosphorylation in nuclear-cytoplasmic trafficking is still unknown. The idea that Nups phosphorylation could regulate protein import and RNA export as a switch that turns the different pathways on/off should be pursued in more detail. As mentioned above, Ran is essential for the regulation of most of the nuclear export and import pathways, because it acts as a cofactor modulating the affinity of importins and exportins for the cargo. The RanGTP cycle is described in detail in Section 6.1. It has been described that EMCV L directly interacts with Ran, and this interaction is abrogated by the insertion of C19A mutation in L [203] . However, the potential role of L/Ran interaction in the modulation of RanGTP cycle and its impact in nuclear import and export pathways have not yet been studied.