The Role Of Translation Initiation Factor EIF3 In Protein Synthesis And Mitochondrial Function

mRNA translation into protein is a fundamental process essential for cell growth and differentiation,nervous system function and memory,aging and a series of diseases,including cancer.As such,translation is one of the most tightly controlled steps in gene expression and closely integrated with nutrient and energy status as well as environmental cues such as stress conditions.Although translation is conceptually separated into discrete biochemical steps-initiation,elongation,termination,and ribosome recycling-more recent evidence suggests that regulation occurs in an integrated fashion in vivo affecting multiple steps simultaneously.One important integrated regulator of mRNA translation is the multi-functional eIF3 complex,which consists of 12 highly conserved subunits.This multi-subunit complex is thought to execute numerous functions in canonical translation initiation,including mRNA recruitment to the 40S ribosome,scanning for the start codon,and inhibition of 60S subunit joining.eIF3 was also found to interact with 40S and 60S ribosomal proteins and translation elongation factors,but a direct involvement in translation elongation has never been demonstrated.We made the unexpected observation that eIF3 remains bound to actively translating 80S ribosomes.Furthermore,eIF3 deficiency reduces early ribosomal elongation speed,particularly on mRNAs encoding proteins associated with membrane-associated functions,resulting in defective synthesis of their encoded proteins and abnormal mitochondrial and lysosomal physiology.Accordingly,heterozygous eIF3e+/-knockout mice accumulate giant 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 normal muscle health.Together,these discoveries led to the novel hypothesis that eIF3 subunits form distinct modules each having mRNA selective functions that integrate translation initiation and elongation in a hitherto unprecedented fashion.In summary,this research will deliver ground-breaking discoveries regarding the mechanistic functions of eIF3 in protein synthesis and homeostasis with implications for understanding its roles in diseases such as cancer.