Eukaryotic initiation factor 6 mediates a continuum between 60S ribosome biogenesis and translation

Abstract

Eukaryotic ribosome biogenesis and translation are linked processes that limit the rate of cell growth. Although ribosome biogenesis and translation are mainly controlled by distinct factors, eukaryotic initiation factor 6 (eIF6) has been found to regulate both processes. eIF6 is a necessary protein with a unique anti-association activity, which prevents the interaction of 40S ribosomal subunits with 60S subunits through its binding to 60S ribosomes. In the nucleolus, eIF6 is a component of the pre-ribosomal particles and is required for the biogenesis of 60S subunits, whereas in the cytoplasm it mediates translation downstream from growth factors. The translational activity of eIF6 could be due to its anti-association properties, which are regulated by post-translational modifications; whether this anti-association activity is required for the biogenesis and nuclear export of ribosomes is unknown. eIF6 is necessary for tissue-specific growth and oncogene-driven transformation, and could be a new rate-limiting step for the initiation of translation.

Figure 1

eIF6 in ribosome biogenesis and translational control. In the nucleolus, eIF6 associates with immature large ribosomal subunits (pre-60S) and other regulatory proteins (trans-acting factors). eIF6 is found during pre-60S subunit maturation in the nucleoplasm and is exported to the cytosol. Here, eIF6 release allows the 60S to join the 40S subunit, and the active, translating 80S complex is formed. eIF6 shuttling between the nucleus and cytoplasm allows the proper formation of pre-60S. Whether eIF6 joins the 60S and prevents its premature association with 40S after the termination of translation is unknown. eIF6, eukaryotic initiation factor 6; PABP, polyA-binding protein.

Figure 2

Unique structure of eIF6. The eIF6 protein is highly conserved and has a unique star-like structure known as pentein, which is formed by five quasi-identical α/β-subdomains (A–E) that enclose a cavity filled by 16 ordered water molecules (Groft et al, 2000). Here we show top and side views of the Saccharomyces cerevisiae structure, in which the cavity is closed. The structure of eIF6 is relatively rigid and has no structural homologue. The S. cerevisiae eIF6 Protein Data Bank access code is 1G62. eIF6, eukaryotic initiation factor 6.

Figure 3

eIF6 release regulates the interaction of the two ribosomal subunits. Two models for eIF6 release have been described for mammals and yeast. In mammalian cells, this event is modulated by the RACK1–PKC complex. PKC is recruited to the 40S subunit by RACK1 and phosphorylates eIF6 on Ser 235, leading to its release from 60S. In yeast, a structural rearrangement of the large subunit is mediated by the Efl1 protein, which facilitates the release of Tif6 from 60S and its subsequent recycling to the nucleolus. Efl1, elongation factor-like 1 protein; eIF6, eukaryotic initiation factor 6; PABP, polyA-binding protein; PKC, protein kinase C; RACK1, receptor for active C kinase 1; Tif6, translation initiation factor 6.

Annarita Miluzio

Anne Beugnet

Viviana Volta

Stefano Biffo