A cyclin-dependent kinase, CDK11/p58, represses cap-dependent translation during mitosis

Sihyeon An,Oh Sung Kwon,Sung Key Jang,Jinbae Yu

doi:10.1007/s00018-019-03436-3

Abstract

During mitosis, translation of most mRNAs is strongly repressed; none of the several explanatory hypotheses suggested can fully explain the molecular basis of this phenomenon. Here we report that cyclin-dependent CDK11/p58—a serine/threonine kinase abundantly expressed during M phase—represses overall translation by phosphorylating a subunit (eIF3F) of the translation factor eIF3 complex that is essential for translation initiation of most mRNAs. Ectopic expression of CDK11/p58 strongly repressed cap-dependent translation, and knockdown of CDK11/p58 nullified the translational repression during M phase. We identified the phosphorylation sites in eIF3F responsible for M phase-specific translational repression by CDK11/p58. Alanine substitutions of CDK11/p58 target sites in eIF3F nullified its effects on cell cycle-dependent translational regulation. The mechanism of translational regulation by the M phase-specific kinase, CDK11/p58, has deep evolutionary roots considering the conservation of CDK11 and its target sites on eIF3F from C. elegans to humans.

Highlights

Translation is the last step of gene expression, and regulation of gene expression at the translational level plays important roles in various biological processes owing to its rapid and reversible nature and the necessity of controlling gene expression spatially
Since CDK11/p58 is expressed during mitosis (Fig. 2b) and interacts with eIF3F (Fig. 3), we investigated whether CDK11/p58 is responsible for the M phasespecific phosphorylation of eIF3F
The results suggest that the hyper-phosphorylation of eIF3F in M phase is solely attributed to CDK11/p58 and that the basal phosphorylation of eIF3F, which remains at the same level across the cell cycle in CDK11 knockdown cells (Fig. 4b), is likely executed by an unknown kinase(s) other than CDK11

Summary

Introduction

Translation is the last step of gene expression, and regulation of gene expression at the translational level plays important roles in various biological processes owing to its rapid and reversible nature and the necessity of controlling gene expression spatially. Translation initiation requires many translation factors and is the major regulation point. The best known example is stress-dependent repression of translation. Various stresses, such as amino acid starvation, ER overloading, oxidative stress, and viral infection, activate corresponding kinases that phosphorylate the alpha subunit of the translation initiation factor, eIF2, which loads the initiator tRNA (Met-tRNAiMet) onto the 40S ribosomal subunit [5]. The eIF2 containing the phosphorylated alpha subunit sequesters eIF2B, which exchanges GDP for GTP on eIF2 for its activation. Sequestration of eIF2B inhibits eIF2-dependent Met-tRNAiMet binding to the 40S ribosomal subunit [6, 7]. Global translation is repressed by various cellular stresses

Methods

Results

Conclusion