Proteolysis of the p220 component of the cap-binding protein complex is not sufficient for complete inhibition of host cell protein synthesis after poliovirus infection

Abstract

Infection of cells with poliovirus results in the complete shutoff of host protein synthesis. It is presumed that proteolysis of the p220 component of the cap-binding protein complex that is required for the translation of host mRNAs is responsible for the shutoff phenomenon. In this paper, we show that when cells are infected with poliovirus in the presence of guanidine or 3-methylquercetin, both inhibitors of poliovirus replication, complete cleavage of p220 occurs by 3.5 h postinfection. However, under these conditions only 55 to 77% of host protein synthesis is suppressed. Results obtained with extracts prepared from poliovirus-infected cells were similar to those obtained in vivo. These results suggest that complete inhibition of host protein synthesis after poliovirus infection requires at least one event in addition to proteolysis of p220. Thus, proteolysis of p220 is probably necessary but not sufficient for total suppression of host protein synthesis after poliovirus infection.

Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E.

“…One can envisage that the cleavage of p220 might result in the loss of the eIF-4E subunit, where the modified eIF-4F remains functional for internal initiation but cap-dependent translation is blocked. However, cleavage of p220 alone is not sufficient for the complete inhibition of host protein synthesis after poliovirus infection (Bonneau and Sonenberg, 1987b). It is thus possible that dephosphorylation of 4E-BPs, and subsequent increased affinity for eIF-4E, also contribute to the shut-off of host protein synthesis.…”

Translational control by viral proteinases

“…Several groups have shown that poliovirus infections carried out in the presence of inhibitors of viral RNA replication (e.g. 2 mM guanidine-HCl, quercitin, monensin) result in complete cleavage of eIF4GI, yet cap-dependent translation is only partly inhibited, usually by about 50% (Bonneau and Sonenberg, 1987;Bovee et al, 1998b;Irurzun et al, 1995;Pérez and Carrasco, 1992). Thus, some fundamental event was missing from the shutoff models that did not occur in the presence of guanidine.…”

Conducting the initiation of protein synthesis: the role of eIF4G

“…Also puzzling is the fact that during the course of poliovirus infection, treatment of cells with various inhibitors of viral replication (e.g. monensin, nigericin or guanidine HCl) results in only a partial inhibition of cellular translation whereas the pool of eIF4GI is substantially degraded (Bonneau and Sonenberg, 1987;Irurzun et al, 1995;Perez and Carrasco, 1992). Conversely, persistent infection of a human erythroleukemic cell line by poliovirus led to substantial degradation of the eIF4GI protein with no concomitant loss of host protein synthesis (Lloyd and Bovee, 1993) and injection of 2A protease into Xenopus oocytes results in only a modest inhibition of endogenous protein synthesis despite complete degradation of endogenous eIF4GI (Keiper and Rhoads, 1997).…”