CDK1/S6K1-PYGO2 axis regulates eIF3D-dependent translational initiation during mitosis

ABSTRACT: mRNA translation represents the conclusive step of the gene expression program, which is crucial in most cellular processes including cell cycle progression, cell growth and proliferation, and is tightly controlled throughout the cell cycle. Although global translation rates are decreased during mitosis, the significance of translation in mitosis resides in the fact that the proteins produced during this phase are vital for the proper progression of mitosis and subsequent cell division. Protein synthesis is driven by translation factors that interact with the ribosome, but translation factors which regulate mitotic translation and their regulatory mechanism remain poorly elucidated. Here we describe a regulatory mechanism of mitotic translation, governed by eIF3D-dependent translation initiation that relies on a novel translation factor PYGO2 downstream of CDK1 and S6K1 signaling pathway. PYGO2 is phosphorylated on serine (S) 40 and S97 by CDK1/Cyclin B1, and on S48 by S6K1 during mitosis. PYGO2 localizes at mitotic spindle and cytosol, interacts with eukaryotic translation initiation factor 3 (eIF3) complex proteins including direct cap-binding protein eIF3D, and promotes cap-binding affinity of eIF3D during mitosis in a manner of CDK1- and S6K1-dependent phosphorylation. Indeed, PYGO2 is required for mRNA translation during mitosis. In the absence of PYGO2 or its phosphorylation on S40, S48 and S97, cells display increased level of mitotic defect due to reduced level of protein synthesis. Moreover, PYGO2 differentially regulates translation of mRNA subsets which are each involved in transcription, translation, RNA processing or ribosome biogenesis. Collectively, our data provide a mechanism how the cells regulate translation of each subset of mRNAs through dynamic signaling pathways that promote eIF3D-dependent translation initiation during mitosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252882 | GEO | 2026/01/01

REPOSITORIES: GEO