eIF3e and eIF3d control expression of riboproteins and key components of the MAPK signaling pathway

ABSTRACT The MAPK cascade plays a key role in transducing extracellular signals into cellular responses. As such, it is unsurprisingly hyperactive in various cancers, primarily due to activating or loss-of-function mutations of its components. Various pathologies, including cancer, are also characterized by deregulated protein synthesis, where imbalanced expression of eIFs is not only a consequence of neoplasia but itself a major contributor to it. eIF3 stands out as the largest, multi-subunit complex with a modular assembly, where aberrant expression of one subunit generates only partially functional subcomplexes. Here, we knocked-down eIF3d, eIF3e and eIF3h in HeLa cells and investigated their impact on differential gene expression by Ribo-Seq. Knock-downs of eIF3d and eIF3e activated the MAPK/ERK1/2 signaling despite reduced protein levels of its multiple components. Depletion of eIF3e and partially eIF3d also increased expression of ribosomal proteins, implicating eIF3 in controlling balanced production of mature ribosomes. Moreover, intact eIF3 also regulates the expression of the proto-oncogene MDM2 and the transcription factor ATF4, both containing short uORFs. eIF3 thus exerts specific translational control over signaling and stress-related transcripts.