eIF3 is a multi-subunit complex with numerous functions in canonical translation initiation, including mRNA recruitment to the 40S ribosome, scanning for the start codon, and inhibition of premature 60S subunit joining 1-3 . eIF3 was also found to interact with 40S and 60S ribosomal proteins and translation elongation factors 4 , but a direct involvement in translation elongation has never been demonstrated. Using ribosome profiling, we found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ~2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote early elongation, eIF3 forms stable protein interactions with 80S ribosomes translating the first ~60 codons and serves as a platform to recruit protein quality control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e +/knockout mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength with age. Hence, in addition to its canonical role in translation initiation, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health.The interaction of the 13 subunit eIF3 complex with mRNA is central to all forms of translation initiation, including cap-dependent and cap-independent mechanisms 5-7 . eIF3 promotes ternary complex recruitment, binding of the 43S pre-initiation complex to mRNA, as well as scanning processivity and fidelity 1,2 . Although eIF3 has traditionally been thought to be released from ribosomes upon 40S-60S subunit joining in vitro 8 , recent evidence in yeast 3 suggested that it can remain associated with 80S ribosomes during translation of short uORFs in order to facilitate re-initiation on downstream ORFs 9 . In addition, pull-down experiments indicated that yeast eIF3 forms stable in vivo interactions with factors involved in translation elongation (40S and 60S ribosomal proteins, eukaryotic elongation factors (eEFs), and tRNA synthetases), suggesting an unexplored role in integrating translation initiation with elongation 4 .
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