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Eukaryotic Initiation Factor 4E (eIF4E) sequestration mediates 4E-BP1 response to rapamycin

Batool, Asiya, Majeed, Sheikh Tahir, Aashaq, Sabreena, Majeed, Rabiya, Shah, Ghazia, Nazir, Nadiem, Andrabi, Khurshid Iqbal
International journal of biological macromolecules 2019 v.125 pp. 651-659
glucose, messenger RNA, nutrients, phosphorylation, rapamycin, translation (genetics)
The cap dependent translation initiation is a tightly controlled process of cooperative ternary complex formation by 4E-BP1, eIF4E and the 5′ cap of eukaryotic mRNA in response to environmental cues like glucose, nutrients and growth factor levels. Based on the well-described effects of mTORC1/rapamycin complex on 4E-BP1 phosphorylation/s, it is generally accepted that rapamycin is a global inhibitor of cap-dependent translation. We have previously shown that 4E-BP1 resistance to rapamycin was overcome by the stoichiometric abundance of S6K1. Now we present evidence that the TOS-bearing amino terminal domain of S6K1 is sufficient to relieve the rapamycin resistance of 4E-BP1 as TOS deleted variants of S6K1, active or inactive with regard to S6K1 activity failed to bring about relief of 4E-BP1 resistance to rapamycin. We also show that the reciprocal inactivation of S6K1 by abundance of 4E-BP1 gets accomplished only with intact TOS motif in the protein. The data presented in this study identifies eIF4E and not Raptor as a cellular factor responsible to regulate rapamycin sensitivity of 4E-BP1 suggesting that the phosphorylation dynamics and rapamycin sensitivity of 4E-BP1 and S6K1 are regulated independently.