Translation Regulation during Mitotic Phase

Abstract

Translation is mediated by numerous factors and serve as a key regulatory pathway of gene expression for living organisms. Regulation of translation is provoked by various cellular responses such as external stimuli, differentiation, and proliferation. The general translation in eukaryotes are controlled in several ways: eIF2a phosphorylation, 4E-BP phosphorylation, mTOR signalling, etc. During mitosis, translation of most mRNAs is strongly repressed. Several hypotheses have been suggested to explain this interesting phenomenon, but none of them fully explains the molecular basis of the translational repression. Here I report a cyclin-dependent CDK11/p58, which is a serine/threonine kinase expressed in large quantity only in M phase, represses general translation through phosphorylation of a subunit (eIF3F) of translation factor eIF3 complex that is essential for translation initiation of most mRNAs. Ectopic expression of CDK11/p58 strongly repressed capdependent translation, and knockdown of CDK11/p58 nullified the translational repression at the M phase. I identified the phosphorylation sites in the eIF3F responsible for the M phase-specific translational repression by CDK11/p58. Alanine substitutions of the CDK11/p58 target sites in the eIF3F nullified the cell cycledependent translational regulation. Considering that the conservation of CDK11 and the target sites on the eIF3F from C. elegans to human, I speculate that the mechanism of translational regulation by a M phase-specific kinase CDK11 has deep evolutionary roots. eIF4GII is referred as just a functional homolog of eIF4GI in mammals, despite their considerable amino acid sequence differences. Here I suggest novel aspects about differences between eIF4GI and eIF4GII in eIF4F complex formation manner. eIF4GII showed higher affinity than eIF4GI in interactions with eIF4E or mRNA 5’ cap. When mTORC1 is inactivated by rapamycin treatment, eIF4GI largely lost its interaction with eIF4E while eIF4GII to eIF4E interaction was sustained. Besides, amino acid starvation or hypoxia driven ER stresses provoked similar phenomena as rapamycin treatment. Interestingly, global translation was no further inhibited during knockdown of eIF4GII in stress conditions, indicating eIF4GII may be related to the translation of specific mRNAs. Moreover, the ratio of eIF4GII association to cap binding complex was increased during neuronal differentiation. Therefore, here I propose that an alternative core protein of eIF4F complex, eIF4GII, drives specific mRNA translation during ER stress and neuron differentiation. In summary, I investigated the molecular basis of general translation control mechanisms in mitosis and stress condition. I showed eIF3F phosphorylation occurs in mitotic phase by CDK11/p58 and its phosphorylation is a key process on mitotic translational repression. I also propose the eIF4GII dependent translation which is provoked in stress and developmental conditions. I believe that these studies provide the novel mechanism of mitotic translational repression and eIF4GII dependent translation.