A new pathway of translational regulation mediated by eukaryotic initiation factor 3

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Abstract
We report a new pathway of translation regulation that may operate in interferon‐treated or virus‐infected mammalian cells. This pathway is activated by P56, a protein whose synthesis is strongly induced by interferons or double‐stranded RNA. Using a yeast two‐hybrid screen, we identified the P48 subunit of the mammalian translation initiation factor eIF‐3 as a protein that interacts with P56. The P56–P48 interaction was confirmed in human cells by co‐immunoprecipitation assays and confocal microscopy. Gel filtration assays revealed that P56 binds to the large eIF‐3 complex that contains P48. Purified recombinant P56 inhibited in vitro translation of reporter mRNAs in a dose‐dependent fashion, and that inhibition was reversed by the addition of purified eIF‐3. In vivo, expression of transfected P56 or induction of the endogenous P56 by interferon caused an inhibition of overall cellular protein synthesis and the synthesis of a transfected reporter protein. As expected, a P56 mutant that does not interact with P48 and eIF‐3 failed to inhibit protein synthesis in vitro and in vivo.