Gandin Valentina, Masvidal Laia, Cargnello Marie, Gyenis Laszlo, McLaughlan Shannon, Cai Yutian, Tenkerian Clara, Morita Masahiro, Balanathan Preetika, Jean-Jean Olivier, Stambolic Vuk, Trost Matthias, Furic Luc, Larose Louise, Koromilas Antonis E, Asano Katsura, Litchfield David, Larsson Ola, Topisirovic Ivan
Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.
Department of Oncology, McGill University, Montreal, Quebec, Canada H3T 1E2.
Nat Commun. 2016 Apr 4;7:11127. doi: 10.1038/ncomms11127.
Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role for CK2 in regulation of translation initiation, whereby CK2 stimulates phosphorylation of eIF2β and simultaneously bolsters eIF4F complex assembly via the mTORC1/4E-BP pathway. These findings imply a previously unrecognized mode of translation regulation, whereby mTORC1 and CK2 coordinate TC and eIF4F complex assembly to stimulate cell proliferation.
三元复合物（TC）和eIF4F复合物组装分别是由eIF2α磷酸化和mTOR/4E-BP途径调控的翻译起始过程中的两个主要限速步骤。然而，TC和eIF4F组装是如何协调的，在很大程度上仍不清楚。我们发现，mTOR抑制在短期应激下被激活的mRNA的翻译，其中TC循环因eIF2α磷酸化而减弱。在急性营养或生长因子刺激期间，mTORC1诱导eIF2β磷酸化并使NCK1募集到eIF2，减少eIF2α磷酸化并促进TC循环。因此，eIF2β介导mTORC1对蛋白质合成和增殖的影响。此外，我们证明了CK2在翻译起始调控中以前未被记录的作用，即CK2刺激eIF2β磷酸化，并同时通过mTORC1/4E-BP途径促进eIF4F复合物组装。这些发现暗示了一种以前未被认识的翻译调控模式，即mTORC1和CK2协调TC和eIF4F复合物组装以刺激细胞增殖。
