A Lipid Transfer Protein Signaling Axis Exerts Dual Control of Cell-Cycle and Membrane Trafficking Systems

• DOI: 10.1016/j.devcel.2017.12.026
• Publication Date: 2018-01-27T01:50:17Z
• Authors: Jin Huang; Carl J. Mousley; Louis Dacquay; Nairita Maitra; Guillaume Drin; Chong He; Neale D. Ridgway; Ashutosh Tripathi; Michael Kennedy; Brian K. Kennedy; Wenshe Liu; Kristin Baetz; Michael Polymenis; Vytas A. Bankaitis
• Keywords: Receptors, Steroid; 0303 health sciences; Saccharomyces cerevisiae Proteins; [SDV]Life Sciences [q-bio]; Cell Cycle; Cell Membrane; 610; Golgi Apparatus; Membrane Proteins; Biological Transport; Endosomes; Saccharomyces cerevisiae; Lipids; 03 medical and health sciences; Cell Movement; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; Phospholipid Transfer Proteins; Histone Acetyltransferases; Signal Transduction

Kes1/Osh4 is a member of the conserved, but functionally enigmatic, oxysterol binding protein-related protein (ORP) superfamily that inhibits phosphatidylinositol transfer protein (Sec14)-dependent membrane trafficking through the trans-Golgi (TGN)/endosomal network. We now report that Kes1, and select other ORPs, execute cell-cycle control activities as functionally non-redundant inhibitors of the G1/S transition when cells confront nutrient-poor environments and promote replicative aging. Kes1-dependent cell-cycle regulation requires the Greatwall/MASTL kinase ortholog Rim15, and is opposed by Sec14 activity in a mechanism independent of Kes1/Sec14 bulk membrane-trafficking functions. Moreover, the data identify Kes1 as a non-histone target for NuA4 through which this lysine acetyltransferase co-modulates membrane-trafficking and cell-cycle activities. We propose the Sec14/Kes1 lipid-exchange protein pair constitutes part of the mechanism for integrating TGN/endosomal lipid signaling with cell-cycle progression and hypothesize that ORPs define a family of stage-specific cell-cycle control factors that execute tumor-suppressor-like functions.