Nucleocytoplasmic Trafficking Perturbation Induced by Picornaviruses

Abstract

Picornaviruses are positive-stranded RNA viruses. Even though replication and translation of their genome take place in the cytoplasm, these viruses evolved different strategies to disturb nucleocytoplasmic trafficking of host proteins and RNA. The major targets of picornavirus are the phenylalanine-glycine (FG)-nucleoporins, which form a mesh in the central channel of the nuclear pore complex through which protein cargos and karyopherins are actively transported in both directions. Interestingly, while enteroviruses use the proteolytic activity of their 2A protein to degrade FG-nucleoporins, cardioviruses act by triggering phosphorylation of these proteins by cellular kinases. By targeting the nuclear pore complex, picornaviruses recruit nuclear proteins to the cytoplasm, where they increase viral genome translation and replication; they affect nuclear translocation of cytoplasmic proteins such as transcription factors that induce innate immune responses and retain host mRNA in the nucleus thereby preventing cell emergency responses and likely making the ribosomal machinery available for translation of viral RNAs.

HSBP1 Is a Novel Interactor of FIP200 and ATG13 That Promotes Autophagy Initiation and Picornavirus Replication

“…Picornaviruses cause a so-called nucleocytoplasmic traffic disorder by modulating the nuclear pore complexes and thereby disrupting the regulated transport of material, i.e., proteins and mRNA, in and out of the nucleus ( Lidsky et al., 2006 ; Lizcano-Perret and Michiels, 2021 ). Interestingly, we also observed a relocalization of GFP-HSBP1 from the cytoplasm into the nucleus upon EMCV infection by fluorescence microscopy ( Figure 4A ).…”

“…We also found that GFP-HSBP1 translocation into the nucleus depends on L since infection with EMCV-Zn, an EMCV strain lacking L ( Hato et al., 2007 ), did not lead to the same change ( Figures S3C, D ). The mechanism underlying nucleocytoplasmic traffic disorders differs between members of the cardioviruses ( Picornaviridae ) like EMCV and members of the enteroviruses ( Picornaviridae ) such as CVB3 and EV71 ( Lizcano-Perret and Michiels, 2021 ). Thus, we tested whether the relocalization of HSBP1 is specific to EMCV or also occurs upon infection with CVB3 and EV71.…”

RNA-Binding Proteins as Regulators of Internal Initiation of Viral mRNA Translation

“…However, several viruses, including picornaviruses, subvert the host nucleocytoplasmic trafficking machinery to their benefit during infection (Figure 2) [334,[351][352][353]. Different viruses, many of which rely on IRES-dependent translation initiation for the synthesis of their proteins, use different mechanisms to co-opt the cell's nucleocytoplasmic trafficking machinery (for reviews, see [334,[351][352][353]). For enteroviruses and rhinoviruses, 2A and 3C proteases are important for the process [191,[354][355][356][357].…”

“…In aphthoviruses, the 3C protease is used [358], while cardioviruses need their L protein [359]. Nucleocytoplasmic protein relocalization during viral infection is not just a spillover event associated with viral infection as control nuclear proteins remain in the nucleus [351][352][353]360]. Proteins from the hnRNP family may, for example, associate with other proteins linked with pre-mRNA metabolism, such as members of the serine/arginine (SR)-rich protein family of splicing factors [336], relocalize as a complex and stimulate viral IRES-mediated translation in the cytoplasm.…”

“…This would be the case of PCBP2 (hnRNPE2) and SRp20 that relocalize together from the nucleus to the cytoplasm and synergistically stimulate PV IRES activity [232,248,249]. Other examples of nuclear proteins that, upon picornaviral infection, relocalize to the cytoplasm where they act as ITAFs are Sam68 [242,361], hnRNP D [255,362,363], hnRNP A1 [360,364], Nucleolin [270,360,365], hnRNPC [360], hnRNP K [360], and La [360], among others, as reviewed in [351,352]; by relocalizing nuclear proteins that act as ITAFs to the cytoplasm, viruses can cope with the need of these factors for viral IRES function.…”