Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Sun, Di; Chen, Shun; Cheng, Anchun; Wang, Mingshu

In contrast to the eukaryotic translation mechanism, picornaviruses take advantage of the IRES element to recruit ribosomal subunits for initiation [58] (Figure 4A ). Reconstitution assays have indicated that assembly of 48S initiation complexes on IRES elements of types I and II (FMDV and EMCV) requires eIF3, eIF4A and the C-terminal end of eIF4G [59] . In addition to eIFs, IRES-transacting factors (ITAFs) including PTB, PCBP2, and Germin 5 contribute to the modulation of IRES activity. Furthermore, 3C pro plays a significant role by cleaving some eIFs and ITAFs to guarantee the internal initiation of translation (Tables 1 and 2) . Picornavirus-infected host cells experience a rapid shut-off of the cap-dependent protein and DNA repair systems. The cleavage of cellular factors as well as inhibition of their expression may explain this phenomenon ( Table 2 ). The picornaviral proteinases, L, 2A and 3C pro , have been reported to primarily function in the cleavage of host translation initiation factors (eIFs). Transient expression assays have shown that eIF4A and eIF4G can be cleaved when FMDV 3C pro is expressed. Furthermore, cleavage by 3C pro is different from that by the FMDV leader protein and 2A pro [61] . Subsequently, it has been demonstrated that L pro and 3C pro can function in the sequential cleavage of eIF4GI in BHK cells after infection with wild-type FMDV [62] . Two forms of eIF4A, namely, eIF4AI and eIF4AII, exist within mammalian cells. FMDV 3C pro cleaves only eIF4AI, which is not related to eIF4AII even though they share 91% sequence identity [63] . In addition, during PV, CVB3 and HRV infection, eIF5B eukaryotic initiation factor is cleaved at a single site (VVEQ↓G), which separates the N-terminal domain from the conserved GTPase domain and C-terminal domain [64] . PCBP2, also known as hnRNP E2, has multiple functions in the post-transcriptional control of host and viral gene expression. The ability of PV to take advantage of PCBP2 in translation and replication has already been discussed [65] , and it has also been observed that PCBP2 is cleaved by 3C pro in HAV. Thus, HAV may regulate protein synthesis and RNA synthesis by 3C pro [66] . In addition to PABP cleavage by 2A pro and PV, HAV and EMCV 3C pro s have also been reported to specifically cleave PABP [67] [68] [69] . A study of EMCV 3C pro suggests that specific PABP cleavage is required for virus replication or that fulllength PABP is not absolutely required for virus replication [69] . The cleavage of Ras GTPaseactivating protein-binding proteins (G3BP1) may be induced by 3C pro to facilitate viral replication after CVB3 infection [70] . Recently, it has been demonstrated that the Sam68 nuclear RNA-binding protein can be cleaved by 3C pro of FMDV, thus allowing 3C pro to redistribute Sam68 to the cytoplasm. Picornavirus-infected host cells experience a rapid shut-off of the cap-dependent protein and DNA repair systems. The cleavage of cellular factors as well as inhibition of their expression may explain this phenomenon ( Table 2 ). The picornaviral proteinases, L, 2A and 3C pro , have been reported to primarily function in the cleavage of host translation initiation factors (eIFs). Transient expression assays have shown that eIF4A and eIF4G can be cleaved when FMDV 3C pro is expressed. Furthermore, cleavage by 3C pro is different from that by the FMDV leader protein and 2A pro [61] . Subsequently, it has been demonstrated that L pro and 3C pro can function in