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.

Keywords: 2A protease; 3C protease; RAN GTPase; karyopherin; leader (L) protein; nuclear pore complex; nucleoporins; picornavirus.

Figure 1

The nuclear pore complex and nucleocytoplasmic transport of proteins.

Figure 2

Picornavirus-induced alteration of the nuclear pore complex. (A) Illustration of the NPC showing alterations triggered by picornaviruses. The proteins forming the different nuclear pore components and some soluble phase proteins are indicated. FG-nucleoporins are in bold characters. Alterations triggered by picornaviruses are depicted as follows. Blue scissors: caspase-dependent degradation (e.g., importins); Red scissors: virus-dependent cleavage; P: phosphorylation. The model proposed to account for NUP phosphorylation by cardioviruses is illustrated: a complex formed between the L protein, RAN and exportins would recruit kinases (e.g., ERK1/2 and p38) to the NPC, where these kinases would induce the phosphorylation of FG-nucleoporins. (B) Zoom on FG-nucleoporins molecular modifications by picornaviruses. Enteroviruses use their 2A^pro and 3C^pro to cleave the FG domains, thereby inducing an opening of the pore. Cardioviruses use their L protein to trigger the phosphorylation of the FG-rich domains of FG-nucleoporins, thereby inducing disorganization of the pore.

Figure 3

Consequences of protein and RNA trafficking perturbation induced by Picornaviruses. (1) Cytoplasmic retention of transcription factors (STAT1/2, IRF3) thereby inhibiting transcriptional induction of cellular genes: e.g., karyopherin subunit α1 cleavage prevents the translocation of STAT1/2 into the nucleus. (2) Nuclear proteins are delocalized to the cytoplasm, where they interact with the viral genome to promote viral genome translation or replication. (3) Blocking of mRNA export, preventing the translation of antiviral proteins, and making the translation machinery available for viral mRNA translation.