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Review
. 2013 Oct;45(10):2158-62.
doi: 10.1016/j.biocel.2013.06.001. Epub 2013 Jun 13.

eIF3f: a central regulator of the antagonism atrophy/hypertrophy in skeletal muscle

Anthony M J Sanchez  1 , Alfredo Csibi, Audrey Raibon, Aurélie Docquier, Julie Lagirand-Cantaloube, Marie-Pierre Leibovitch, Serge A Leibovitch, Henri Bernardi
Affiliations
Review

eIF3f: a central regulator of the antagonism atrophy/hypertrophy in skeletal muscle

Anthony M J Sanchez et al. Int J Biochem Cell Biol. 2013 Oct.

Abstract

The eukaryotic initiation factor 3 subunit f (eIF3f) is one of the 13 subunits of the translation initiation factor complex eIF3 required for several steps in the initiation of mRNA translation. In skeletal muscle, recent studies have demonstrated that eIF3f plays a central role in skeletal muscle size maintenance. Accordingly, eIF3f overexpression results in hypertrophy through modulation of protein synthesis via the mTORC1 pathway. Importantly, eIF3f was described as a target of the E3 ubiquitin ligase MAFbx/atrogin-1 for proteasome-mediated breakdown under atrophic conditions. The biological importance of the MAFbx/atrogin-1-dependent targeting of eFI3f is highlighted by the finding that expression of an eIF3f mutant insensitive to MAFbx/atrogin-1 polyubiquitination is associated with enhanced protection against starvation-induced muscle atrophy. A better understanding of the precise role of this subunit should lead to the development of new therapeutic approaches to prevent or limit muscle wasting that prevails in numerous physiological and pathological states such as immobilization, aging, denervated conditions, neuromuscular diseases, AIDS, cancer, diabetes. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: Cell growth; MAFbx/atrogin-1; Protein translation; Skeletal muscle; eIF3f.

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Figures

Fig. 1
Fig. 1
Physical and functional links between eIF3f, mTOR-raptor, S6K1 and MAFbx/atrogin-1 in skeletal muscle. The leucine charged domain (LCD) of the ubiquitin ligase MAFbx/atrogin-1 physically interacts with the Mov34 domain of eIF3f and contributes to its ubiquitination in the C-terminal region and its subsequent degradation by the proteasome during muscle wasting. The Mov34 domain also interacts with the inactive hypophosphorylated form of S6K1. Under nutrient rich conditions, mTOR/raptor complex binds to the TOS motif of eIF3f and, thus can phosphorylate and activate S6K1. Active S6K1 is released from eIF3 complex leading to increased protein synthesis. In this model, eIF3f acts as a scaffolding protein allowing mTORC1-dependent activation of S6K1 upon insulin or growth hormone stimulation of muscle cells.
Fig. 2
Fig. 2
eIF3f is at the crossroads between the protein synthesis and protein degradation signaling pathways in skeletal muscle. Upon IGF-1 axis activation, the IGF-1 receptor becomes phosphorylated and recruits IRS1, leading to the activation of the lipid kinase PI3K. PI3K catalyzes the transfer of a phosphate group to the membrane-bound PIP2. Phosphorylation of PIP2 generates PIP3, which recruits two additional kinases, Akt and PDK1. Akt is bound and activated by phosphorylation at Thr-308 by PDK1. Akt inactivates TSC1/TSC2 complex, a Rheb inhibitor, by phosphorylation. Finally, mTOR activated by Rheb, binds to the scaffold protein eIF3f and exerts its activity on protein synthesis by phosphorylation of the S6K1 protein. mTOR in association with rictor phosphorylates and fully activates Akt on Ser-473. While FoxOs transcription factors are directly phosphorylated and inhibited by Akt via 14-3-3 binding in response to insulin/growth factor stimulation, under condition of energy stress, dephosphorylation of FoxO factors leads to its nuclear entry and E3 ubiquitin ligase MAFbx/atrogin-1 expression. Proteasomal degradation of eIF3f mediated by the overexpressed MAFbx/atrogin-1 under starvation and diseases is leading to decreased protein synthesis and muscle wasting. Abbreviations not defined in the text: IGF-1: insulin like growth factor 1; IRS1: insulin receptor substrate 1; PDK1: phosphoinositide-dependent protein kinase-1; PI3K: phosphatidylinositol 3-kinase; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol 3,4,5-triphosphate; Rheb: ras homologous enriched in brain; TSC1/2: tuberous sclerosis complex1/2.
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