| Cells from higher eukaryotes must assimilate signals as diverse as nutrient and growth factor availability, energetic supply, and stress to commit to grow (accrue mass) and proliferate. Protein synthesis is a major contributor to cellular mass and, consequently, to the decision to enter the cell cycle. Translational control, particularly by the mTORC1 pathway, is a significant event in integrating the responses required to maintain cellular, organ, and organismal size. Alterations in mTORC1 signaling in particular, or to translation in general, result in a variety of pathologies including tumorigenesis and metabolic disorders. However, the complex functions of translation initiation factors in normal cells are not well understood. A key component of global translational initiation is the eukaryotic initiation factor (eIF)4GI, which bridges mRNAs with ribosomes. Surprisingly, we show that significant reduction of eIF4GI levels only modestly reduces overall protein synthesis in cells, but selectively inhibits translation of key mRNAs involved in cell growth, proliferation and bioenergetics, a large proportion of which are excluded from polyribosomes due to the presence of multiple upstream open reading frames. eIF4GI reduction partially phenocopies nutrient-starved or mTOR-inhibited cells, impairs cytokinesis, proliferation rates, cellular bioenergetics and mitochondrial activity, and promotes autophagy. High levels of eIF4GI facilitate translation of mRNAs in the nutrient-sensing pathway for cell growth and proliferation, which is not redundant with other eIF4G family members and has features distinct from mTOR inhibition. The elevated levels of eIF4GI observed in breast cancers might promote transformation in part by prevention of autophagy and release from control of nutrient sensing.;Activation of mTORC1, as occurs in the presence of growth factors, typically correlates with increased translation rates and phosphorylation of multiple targets including eIF4GI. We find, paradoxically, that protein synthesis is severely downregulated and eIF4GI hypophosphorylated during mitosis despite high activity of the mTORC1 network. None of the known activators of mTORC1 are active during mitosis. Instead, we find that raptor, an adaptor factor of mTORC1, is specifically hyperphosphorylated during mitosis, which correlates with mTORC1 activity toward some of its substrates. We observe that raptor is likely phosphorylated by multiple kinases, including cdc2 and GSK3, in mitotic cells. We propose that mTORC1 activity during mitosis may prime the translational apparatus for increased protein synthesis upon progression to G1. Additionally, mTORC1 may have yet to be defined roles during G2/M, since a partially non-phosphorylatable raptor mutant arrests cells at G2. These findings expose a new mechanism of cell-cycle specific mTORC1 regulation and function. |
