The Underlying Physiology of a Lipid Transfer Protein Tug‐of‐War in the Endosomal System

The yeast Kes1 is a member of the highly conserved oxysterol binding protein (OSBP) superfamily, and it functions a negative regulator of membrane and lipid trafficking through the yeast trans‐Golgi network (TGN) and endosomal systems. In this capacity, Kes1 opposes the action of the phosphatidylinositol transfer protein Sec14 which promotes TGN/endosomal trafficking. The logic for this TGN/endosomal tug‐of‐war is not at all understood. Although Kes1 is reported to serve as a carrier protein that transports sterols between intracellular membranes in vivo, how this activity is functionally employed in regulating TGN/endosomal dynamics is unknown. I will discuss our recent findings which identify Kes1 as a sterol‐regulated clamp on phosphatidylinositol‐4‐phosphate signaling in the TGN/endosomal system. Our data further demonstrate that the Kes1 rheostat coordinates endosomal lipid metabolism with TORC1 signaling and transcriptional control of nitrogen sensing. We find this circuit interfaces endosomal sphingolipid metabolism with activity of Gcn4 ‐‐ the transcription factor primarily responsible for control of amino acid homeostasis via the general amino acid control pathway. We posit Kes1, and other Kes1‐like OSBPs, couple endosomal trafficking and lipid signaling with a fine‐tuning of eukaryotic cell growth control.