The m Subunit of Murine Translation Initiation Factor elF3 Maintains the Integrity of the elF3 Complex and Is Required for Embryonic Development, Homeostasis, and Organ Size Control

Background: eIF3m is a non-core subunit of eIF3. Results: eIF3m deficiency in mice results in animal death and instability of other eIF3 subunits; haploinsufficiency reduces organ size. Conclusion: eIF3m is critical for eIF3 structure and function. Significance: Understanding the mechanism of eIF3 complex formation and its role in embryonic development and homeostasis is crucial for determining the physiological function of this eukaryotic translation factor. Mammalian eIF3 is composed of 13 subunits and is the largest eukaryotic initiation factor. eIF3 plays a key role in protein biosynthesis. However, it is not fully understood how different subunits contribute to the structural integrity and function of the eIF3 complex. Whether eIF3 is essential for embryonic development and homeostasis is also not known. Here, we show that eIF3m null embryos are lethal at the peri-implantation stage. Compound heterozygotes (eIF3m(flox/-)) or FABP4-Cre-mediated conditional knock-out mice are lethal at mid-gestation stages. Although the heterozygotes are viable, they show markedly reduced organ size and diminished body weight. Acute ablation of eIF3m in adult mouse liver leads to rapidly decreased body weight and death within 2 weeks; these effects are correlated with a severe decline of protein biogenesis in the liver. Protein analyses reveal that eIF3m deficiency significantly impairs the integrity of the eIF3 complex due to down-regulation of multiple other subunits. Two of the subunits, eIF3f and eIF3h, are stabilized by eIF3m through subcomplex formation. Therefore, eIF3m is required for the structural integrity and translation initiation function of eIF3. Furthermore, not only is eIF3m an essential gene, but its expression level is also important for mouse embryonic development and the control of organ size.