Modification of eukaryotic initiation factor 4F during infection by influenza virus

Abstract

Influenza virus infection of cells is accompanied by a striking shutoff of cellular protein synthesis, resulting in the exclusive translation of viral mRNAs. The mechanism for control of cellular protein synthesis by influenza virus is poorly understood, but several translation properties of influenza virus mRNAs which are potentially involved have been described. Influenza virus mRNAs possess the surprising ability to translate in the presence of inhibitory levels of inactive (phosphorylated) eukaryotic initiation factor 2 (eIF-2). In addition, influenza virus mRNAs were shown to be capable of translating in cells during the late phase of adenovirus infection but not in cells infected by poliovirus. Since both adenovirus and poliovirus facilitate virus-specific translation by impairing the activity of initiation factor eIF-4F (cap-binding protein complex) but through different mechanisms, we investigated the translation properties of influenza virus mRNAs in more detail. We show that influenza virus infection is associated with the significant dephosphorylation and inactivation of eIF-4E (cap-binding protein), a component of eIF-4F, and accordingly that influenza virus mRNAs possess a moderate ability to translate by using low levels of eIF-4F. We also confirm the ability of influenza virus mRNAs to translate in the presence of high levels of inactive (phosphorylated) eIF-2 but to a more limited extent than reported previously. We suggest a potential mechanism for the regulation of protein synthesis by influenza virus involving a decreased requirement for large pools of active eIF-4F and eIF-2.

iTRAQ-based comparative proteomic analysis of Vero cells infected with virulent and CV777 vaccine strain-like strains of porcine epidemic diarrhea virus

“…Encephalomyocarditis virus [42], vesicular stomatitis virus [43], or adenovirus [44] infection restrained the cap-dependent translation by promoting the 4EBP1 hypophosphorylation. Influenza virus infection was also reported to decrease the abundance of phosphorylated eIF4E, which might assist to inhibit host translation [45]. Treated with rapamycin, a specific inhibitor of mTOR, the PRRSV titer was dramatically enhanced in host cells than the mock-treated [46].…”

Chapter 3 Virus Versus Host Cell Translation

“…7) (Pyronnet et al, 1999;Raught and Gingras, 2007). Uninfected cells growing exponentially typically possess roughly equal amounts of phosphorylated and nonphosphorylated forms of eIF4E (Feigenblum and Schneider, 1993) and the ratio shifts toward the phosphorylated form of eIF4E following treatment of the cells with growth factors, hormones, and mitogens (Flynn and Proud, 1995;Joshi et al, 1995;Makkinje et al, 1995). However, the functional role of eIF4E phosphorylation remains elusive.…”

“…Adenovirus mediates the quantitative dephosphorylation of eIF4E (up to 95% of the total eIF4E) leading to suppression of cellular protein synthesis (Fig. 7) (Feigenblum and Schneider, 1993). The Adenovirus late protein designated 100K is synthesized at high levels at the onset of the late phase of infection (Bablanian and Russell, 1974;Oosterom-Dragon and Ginsberg, 1980).…”

“…7). Thus, Influenza virus mRNAs that are capped via capsnatching and polyadenylated (Herz et al, 1981;Krug et al, 1979;Luo et al, 1991) are translated efficiently under conditions of partial inactivation of eIF4F (Feigenblum and Schneider, 1993) when host protein synthesis is blocked (Katze and Krug, 1990). Several studies have shown that the NS1 viral protein selectively promotes translation of viral mRNAs by increasing their rate of initiation (de la Luna et al, 1995;Enami et al, 1994;Katze et al, 1986;Park and Katze, 1995) and interacts with PABP and eIF4GI (one of the two isoforms of eIF4G in animals) in viral mRNA translation initiation complexes (Aragó n et al, 2000;Burgui et al, 2003).…”

“…Phosphorylation of eIF4G eIF4G is 10-fold more phosphorylated in Influenza virus-infected than in noninfected cells and phosphorylated eIF4G still interacts with eIF4A and eIF4E. Cleavage of eIF4G by the Poliovirus 2Apro inhibits translation of the Influenza virus mRNAs (Feigenblum and Schneider, 1993;Garfinkel and Katze, 1992). Phosphorylation of eIF4G in HCMV-infected cells is one of the mechanisms that enhances eIF4F activity during the viral replication cycle (Kudchodkar et al, 2004;Walsh et al, 2005).…”