Role of translation initiation factor 4G in lifespan regulation and age-related health

Highlights

• We review the role of eIF4G in translation initiation.

• We examine eIF4G with regards to expression timing, tissue-specificity, and form.

• The role of eIF4G in promoting longevity and impact on disease is explored.

• Specific forms of eIF4G across species are compared.

Abstract

Inhibiting expression of eukaryotic translation initiation factor 4G (eIF4G) arrests normal development but extends lifespan when suppressed during adulthood. In addition to reducing overall translation, inhibition alters the stoichiometry of mRNA translation in favor of genes important for responding to stress and against those associated with growth and reproduction in C. elegans. In humans, aberrant expression of eIF4G is associated with certain forms of cancer and neurodegeneration. Here we review what is known about the roles of eIF4G in molecular, cellular, and organismal contexts. Also discussed are the gaps in understanding of this factor, particularly with regard to the roles of specific forms of expression in individual tissues and the importance of understanding eIF4G for development of potential therapeutic applications.

Introduction

While the functional importance of many translation factors is known in a general sense, more appreciation is being given to their role in determining which mRNAs are given preference for translation, both spatially and temporally, under different conditions. Regulating gene expression at the level of translation acts as an important point of control for diverse processes including growth, cellular differentiation, programmed cell death, and for responding to environmental changes. Most of this control is exerted during the steps immediately preceding peptide synthesis, called translation initiation, which is usually the rate-limiting step of mRNA translation (Hershey et al., 2012).

Some of the interest in the specificity of mRNAs selected for translation has undoubtedly been generated by studies carried out in animal models showing that altering expression of translation factors and machinery can increase lifespan (Chen et al., 2007, Chiocchetti et al., 2007, Curran and Ruvkun, 2007, Hansen et al., 2007, Henderson et al., 2006, Pan et al., 2007, Steffen et al., 2008, Syntichaki et al., 2007). Reducing eukaryotic translation initiation factor 4G (eIF4G) in yeast (Smith et al., 2008) and during adulthood in nematodes (Curran and Ruvkun, 2007, Hansen et al., 2007, Henderson et al., 2006, Pan et al., 2007) leads to a robust increase in lifespan. In mammals, elevated expression of eIF4G is associated with cancer. However, regular eIF4G expression is essential early in life for a normal rate of growth. In addition, diminished levels under certain conditions may lead to neurodegeneration. Here, we briefly review the general role of eIF4G in translation initiation and then discuss what is known about the functional importance of the timing, tissue-specificity, and form (homolog, splice variant, or cleavage product) of this factor, especially with regard to lifespan determination and age-related disease.

Regulation of protein synthesis is essential during organismal development and for responding to environmental input. Translation involves an intricate three stage process of initiation, elongation, and termination. Although translation is subject to regulation at each stage, the rate-limiting step is usually initiation, which centers on recruitment of ribosomal subunits to mature mRNA (Hershey et al., 2012). Translation initiation involves protein-RNA and protein-protein interactions synchronized by multiple translation initiation factors. eIF4G acts as a major hub in initiation and mediates recruitment of additional initiation factors, providing a scaffold for ribosome/mRNA-bridging (Sonenberg et al., 1978).mRNA is co-transcriptionally modified by the addition of a methyl-guanosine (m7GpppX) on the 5′ end, which protects the mRNA from exonuclease activity (Izaurralde et al., 1992) and serves to recruit factors important for initiating translation (Muthukrishnan et al., 1975). The methyl-guanosine addition to the transcript is called the “5′ cap” and translation predominately occurs as a cap-dependent process. Although capped-mRNA is favored for protein synthesis, translation can occur in a cap-independent process that relies on alternate mRNA features (Svitkin et al., 2005). eIF4G plays a crucial role in both processes.

In cap-dependent translation, the cap-binding protein eIF4E binds to eIF4G, which further enhances the affinity of eIF4E for the cap (Haghighat and Sonenberg, 1997). eIF4G also helps recruit the mRNA helicase eIF4A. Together, these three factors make up eIF4F, also known as the cap-binding complex. Through this complex, eIF4G bridges the 5′ untranslated region (UTR) with the polyadenylated 3′ UTR via polyA binding protein (PABP). Association of PABP with eIF4G induces mRNA circularization so that eIF4E at the 5′ cap links with the PABP and the 3′ tail (Tarun Jr and Sachs, 1996). Circularization of mRNA enhances initiation and mRNA stability (Gallie, 1991).

Once the cap-binding complex has bound and circularized the mRNA, eIF4G then helps mediate recruitment of the 40S ribosomal subunit to the mRNA through its association with ribosomal binding protein eIF3 (Lamphear et al., 1995). Prior to this recruitment, the 40S ribosomal subunit associates with eIF3, mRNA scanning proteins eIF1A and eIF1, and the ternary complex, composed of eIF2, GTP, and the methionyl-tRNA initiator (met-tRNAi), together forming the 43S pre-initiation complex (Marchione et al., 2013). eIF3 affixes the 43S pre-initiation complex onto the mRNA, assisted through eIF4G and eIF4E interactions (Etchison et al., 1982, Magnuson et al., 2012). The joined mRNA, pre-initiation complex, and eIF4F complex comprise the 48S pre-initiation complex. The 48S pre-initiation complex scans the 5′ UTR and migrates in a 5′–3′ fashion assisted by the selectivity of eIF1A and eIF1 for the start codon. Upon identification of the start codon, eIF5 triggers initiation by stimulating eIF2 hydrolysis of the ternary complex GTP and then detachment of all 40S-bound initiation factors (Unbehaun et al., 2004). Hydrolysis of GTP from the ternary complex triggers dissociation of initiation factors in the 48S pre-initiation complex and positions met-tRNAi into the P-site on the 40S ribosomal subunit associated with the start codon (Unbehaun et al., 2004). Ribosomal protein S6 within the 40S subunit is phosphorylated by S6 kinase, promoting the joining of both the 40S and 60S subunits, and formation of the 80S ribosome (Jefferies et al., 1994, Magnuson et al., 2012). Successful assembly of the ribosome completes initiation and protein synthesis begins, leaving eIF4G and other initiation factors available to begin a new round of translation initiation.

Cap-independent translation may take place if an internal ribosomal entry site (IRES) is present within the 5′ UTR of the mRNA (Pelletier and Sonenberg, 1988). However, capped mRNAs compete for translation against IRES-containing mRNAs (Svitkin et al., 2005). In the presence of an IRES, eIF4G is capable of initiating translation in the absence of a functional 5′ cap-binding complex (Ali et al., 2001), as is the case when eIF4E is sequestered by eIF4E Binding Protein 1 (4EBP1). When available eIF4E becomes limited, the sub-complex eIF4G/4A is able to bind to IRES-containing mRNAs to mediate translation (Svitkin et al., 2005). If eIF4G is unable to bind eIF4A, then IRES directed translation is abrogated (Lomakin et al., 2000). Therefore eIF4G plays an important role in both cap-dependent and cap-independent mediated translation.