Review
eIF6 anti-association activity is required for ribosome biogenesis, translational control and tumor progression

https://doi.org/10.1016/j.bbagrm.2014.09.010Get rights and content

Highlights

  • eIF6 is necessary for biogenesis and maturation of 60S ribosomal subunit.

  • eIF6 is an anti-association factor that prevent improper joining of 80S complex.

  • eIF6 is necessary for initiation of translation in response to insulin/growth factors.

  • eIF6 is rate limiting for tumor growth, in vivo.

  • eIF6 gain-of-function mutants rescue the lethal phenotype caused by Sbds deficiency.

Abstract

Here we discuss the function of eukaryotic initiation factor 6 (eIF6; Tif6 in yeast). eIF6 binds 60S ribosomal subunits and blocks their joining to 40S. In this context, we propose that eIF6 impedes unproductive 80S formation, namely, the formation of 80S subunits without mRNA. Genetic evidence shows that eIF6 has a dual function: in yeast and mammals, nucleolar eIF6 is necessary for the biogenesis of 60S subunits. In mammals, cytoplasmic eIF6 is required for insulin and growth factor-stimulated translation. In contrast to other translation factors, eIF6 activity is not under mTOR control. The physiological significance of eIF6 impacts on cancer and on inherited Shwachman–Bodian–Diamond syndrome. eIF6 is overexpressed in specific human tumors. In a murine model of lymphomagenesis, eIF6 depletion leads to a striking increase of survival, without adverse effects. Shwachman–Bodian–Diamond syndrome is caused by loss of function of SBDS protein. In yeast, point mutations of Tif6, the yeast homolog of eIF6, rescue the quasi-lethal effect due to the loss of the SBDS homolog, Sdo1. We propose that eIF6 is a node regulator of ribosomal function and predict that prioritizing its pharmacological targeting will be of benefit in cancer and Shwachman–Bodian–Diamond syndrome. This article is part of a Special Issue entitled: Translation and Cancer.

Introduction

eIF6 (eukaryotic Inititiation Factor 6) activity was first described by the pioneering works of the laboratories of Spremulli [57] and Maitra [70] that described a ribosomal antiassociation activity. Cloning of the gene occurred only in the late '90s [6], [64]. From that moment, a limited number of thorough investigations unveiled the peculiar properties of this protein, which makes it a master regulator of translation and tumor progression, in vivo.

Section snippets

eIF6 structure and expression: the basics

eIF6 is an evolutionarily conserved protein of 245 amino acids, 77% identical between yeasts and humans [6]. Truncated isoforms of eIF6 are present in mammalian nucleotide databases, but they have never been observed at the protein level (Biffo, unpublished observations). Despite of conservation, the primary sequence of eIF6 has no homologs or conserved motifs. No evidence for gene duplication exists, suggesting a strong pressure for tight gene dosage, an expectation confirmed by studies in

eIF6 function in ribosome biogenesis

eIF6 localizes both in the nucleolus, where it is enriched in the perinucleolar region, and in the cytoplasm [32], [59]. The presence of eIF6 in the nucleolus supports a role in ribosome biogenesis. Ribosome biogenesis is a conserved process in eukaryotes [19], [33]. In S. cerevisiae, the pathway begins with transcription of the 35S and 5S ribosomal RNA (rRNA) precursors by RNA polymerases I and III, respectively. The association of ribosomal proteins and pre-ribosomal factors with nascent

eIF6 antiassociation activity in translation in normal tissues

eIF6 inhibits the association of 40S and 60S ribosomal subunits into 80S, in vitro [57], [70]. Low concentrations of eIF6 have a slight stimulatory effect on translation, in vitro [57], [70], whereas high concentrations of either eIF6 [11] or aIF6, the Archibacteria homolog [5], inhibit translation. These results suggest that the antiassociation activity of eIF6 needs to be regulated by cellular factors in order to be functional and to avoid translation inhibition. However, it is evident that

Model of eIF6 release from the 60S

Since the binding of eIF6 to the large 60S subunit is mutually exclusive with 40S joining and translation, a release mechanism leading to its dissociation must exists. Two models have been proposed [39], but further work is needed because the picture is still unclear. The first model sustains that the release of eIF6 from 60S is mediated by the SBDS-efl1 complex. Efl1 is a cytoplasmic GTPase homologous to the bacterial ribosomal elongation factor EF-G/EF-2 [61]. The deletion of Efl1 results in

eIF6 in cancer

Increased rates of protein synthesis have been associated with cell growth and transformation [56], but alterations in the ribosomal machinery have been considered for a long time only a by-product of transformation and tumor growth. This view was challenged in recent years by genetic evidence demonstrating that ribosomal alterations modulate tumorigenesis [34], [66]. Enlargement of eIF6 containing nucleoli is a feature of aggressive colorectal tumors [59]. eIF6 is rate limiting for

Shwachman–Bodian–Diamond (SDS) syndrome

The insufficiency of either ribosomal proteins or transacting factors in ribosome biogenesis can result in increased susceptibility to cancer, despite a general reduction in growth capability. This is evident, for instance, in Shwachman–Diamond syndrome (SDS) where neutropenia, exocrine pancreas dysfunction and metaphyseal chondrodysplasia are accompanied by an increased risk of developing myelodysplastic syndrome and acute myeloid leukemia [42]. SDS is an autosomal recessive disorder caused by

Concluding remarks and controversies

Based on our knowledge, we conclude that the anti-association activity of eIF6 acts at two different levels: (1) biogenesis of 60S subunit and export from the nucleus to the cytoplasm and (2) translational control. How the anti-association/dissociation activity functions at the level of translation initiation is still obscure. The specific effects of eIF6 inhibition suggest that somehow 60S availability affects the specific translation of mRNAs. Perhaps reinitiation at uORFs sequences or

Acknowledgements

Work in our laboratory has been generously funded by AIRC IG2011, AICR 13-0045, Fondazione Buzzi UNICEM and TELETHON GGP10012.

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