eIF-Three to Tango: emerging functions of translation initiation factor eIF3 in protein synthesis and disease

Abstract

<jats:title>Abstract</jats:title> <jats:p>Studies over the past three years have substantially expanded the involvements of eukaryotic initiation factor 3 (eIF3) in messenger RNA (mRNA) translation. It now appears that this multi-subunit complex is involved in every possible form of mRNA translation, controlling every step of protein synthesis from initiation to elongation, termination, and quality control in positive as well as negative fashion. Through the study of eIF3, we are beginning to appreciate protein synthesis as a highly integrated process coordinating protein production with protein folding, subcellular targeting, and degradation. At the same time, eIF3 subunits appear to have specific functions that probably vary between different tissues and individual cells. Considering the broad functions of eIF3 in protein homeostasis, it comes as little surprise that eIF3 is increasingly implicated in major human diseases and first attempts at therapeutically targeting eIF3 have been undertaken. Much remains to be learned, however, about subunit- and tissue-specific functions of eIF3 in protein synthesis and disease and their regulation by environmental conditions and post-translational modifications.</jats:p>

eIF3 Associates with 80S Ribosomes to Promote Translation Elongation, Mitochondrial Homeostasis, and Muscle Health

“…While all eukaryotic mRNAs carry a m7G cap, only as few as ~200 mRNAs appear to depend on the eIF4E cap binding protein (Hsieh et al, 2012;Morita et al, 2013;Thoreen et al, 2012;Truitt et al, 2015;Yanagiya et al, 2012), pointing to the existence of alternative noncanonical initiation pathways. Recent studies have implicated the 13-subunit eIF3 complex -the largest of the eukaryotic initiation factors -in several non-canonical modes of initiation (Wolf et al, 2019). Using PAR-CLIP, eIF3 was shown to regulate the translation of hundreds of mRNAs through interaction with structured mRNA motifs located in 5'-UTRs (Lee et al, 2015).…”

“…eIF3 binding sites in mRNA frequently overlap with sites of N6 methyl adenosine (m6A) modification, and eIF3 was shown to bind to m6A either directly or through m6A reader and writer proteins (Choe et al, 2018;Meyer et al, 2015;Shi et al, 2017;Wang et al, 2015). Thus, eIF3 now appears to be involved in many different forms of canonical and non-canonical translation initiation, promoting ternary complex recruitment, binding of the 43S pre-initiation complex to mRNA, closed loop formation as well as scanning processivity and fidelity (Hinnebusch, 2017;Valášek et al, 2017;Wolf et al, 2019).…”

eIF3k Domain-Containing Protein Regulates Conidiogenesis, Appressorium Turgor, Virulence, Stress Tolerance, and Physiological and Pathogenic Development of Magnaporthe oryzae Oryzae

“…Also, the interaction of eIf3 with the eIF2/GTP/Met-tRNAi TC promotes ribosomal recycling by inhibiting the interaction between the 60S subunits and the 43S complex after recycling ( Jackson et al, 2010 ; Hashem et al, 2013 ). The regulatory influence of the eIF3 complex extends across multiple stages of the initiation process, such as charging of tRNAs associated with the 40S ribosomal subunit and also facilitates the loading of charged 40S onto the mRNAs harboring the methylated guanosine cap at the 5′ untranslated region (UTR) by forming a complex with eIF4F ( Jeong et al, 2019 ; Wolf et al, 2020 ). The eIF3 complex also influences both the scanning and the recognition of the start codon on the mRNA ( Unbehaun et al, 2004 ; Jackson et al, 2010 ).…”

“…Currently, eIF3 subunits are classified as essential (conserved, thus, present in all eukaryotes) and non-essential (non-conserved across eukaryotes) ( Smith et al, 2016 ; Wolf et al, 2020 ). In mammals, the eIF3 complex consists of 11–13 subunits (eIF3a, eIF3b, eIF3c, eIF3d, eIF3e, eIF3f, eIF3g, eIF3h, eIF3i, eIF3j, eIF3k, eIF3n, and eIF3m).…”

Unbiased screen of human transcriptome reveals an unexpected role of 3′UTRs in translation initiation

“…These CiTI-binding proteins formed a densely-connected protein-protein interaction network with key functions in translation initiation and RNA processing (Fig. 3b), including many components in the eIF2 or eIF3 complex that functions as a multi-tasking machine to promote translation 39 . Interestingly, the newly identified CiTI-binding proteins also include DHX29 (Fig.…”