Abstract
Members of the p56 family of mammalian proteins are strongly induced in virus-infected cells and in cells treated with interferons or double-stranded RNA. Previously, we have reported that human p56 inhibits initiation of translation by binding to the "e" subunit of eukaryotic initiation factor 3 (eIF3) and subsequently interfering with the eIF3/eIF2.GTP.Met-tRNAi (ternary complex) interaction. Here we report that mouse p56 also interferes with eIF3 functions and inhibits translation. However, the murine protein binds to the "c" subunit, not the "e" subunit, of eIF3. Consequently, it has only a marginal effect on eIF3.ternary complex interaction. Instead, the major inhibitory effect of mouse p56 is manifested at a different step of translation initiation, namely the binding of eIF4F to the 40 S ribosomal subunit.eIF3.ternary complex. Thus, mouse and human p56 proteins block different functions of eIF3 by binding to its different subunits.
Highlights
One of the key features of the innate immune response is the induction of numerous cellular genes in response to viral stress
We have shown recently [4] that the inhibitory activity of human p56 occurs at the step of ternary complex stabilization by eukaryotic initiation factor 3 (eIF3), a key step in the initiation pathway for protein synthesis in eukaryotes
EIF3l, the exact stoichiometry and arrangement of the subunits are poorly understood [5]. eIF3 has many functions in translation initiation, one of which is to serve as a ribosome dissociation factor by binding to the 40 S ribosomal subunit and preventing its re-association with 60 S subunits [6, 7]. eIF3 plays a role in stabilizing interactions with other components of the initiation pathway such as the ternary complex that consists of eIF21⁄7GTP1⁄7Met-tRNAi as well as stabilizing the formation of the 43 S complex that is formed when the ternary complex joins the 40 S ribosome [8, 9]
Summary
One of the key features of the innate immune response is the induction of numerous cellular genes in response to viral stress. Human p56 (Hup56) has been shown to act as an inhibitor of protein synthesis through its association with the “e” subunit of eukaryotic initiation factor 3 (eIF3 1; the e subunit is known as p48 or Int6) [2, 3]. By extending the in vitro protein synthesis studies that showed that Hup can inhibit initiation of translation by interfering with eIF3 function, we followed a systematic investigation to reveal that all functions of eIF3 are not blocked by Hup; it blocks only one specific step, namely the stabilization of the ternary complex of eIF21⁄7GTP1⁄7Met-tRNAi. Hup does not interfere with the interactions of eIF3 with 40 S ribosomal subunits or eIF4F. Mup inhibited a function of eIF3 that is different from the one inhibited by Hup
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