Up-regulation of Osh6 boosts an anti-aging membrane trafficking pathway toward vacuoles

Members of the family of oxysterol-binding proteins mediate non-vesicular lipid transport between membranes and contribute to longevity in different manners. We previously found that a 2-fold up-regulation of Osh6, one of seven yeast oxysterol-binding proteins, remedies vacuolar morphology defects in mid-aged cells, partly down-regulates the target of rapamycin complex 1 (TORC1), and increases the replicative lifespan. At the molecular level, Osh6 transports phosphatidylserine (PS) and phosphatidylinositol-4-phosphate (PI4P) between the endoplasmic reticulum (ER) and the plasma membrane (PM). To decipher how an ER-PM working protein controls vacuolar morphology, we tested genetic interactions between OSH6 and DRS2, whose protein flips PS from the lumen to the cytosolic side of the Golgi, the organelle between ER and vacuoles in many pathways. Up-regulated OSH6 complemented vacuolar morphology of drs2Δ and enriched PI4P on the Golgi, indicating that Osh6 also works on the Golgi. This altered PI4P-enrichment led to a delay in the secretion of the proton ATPase Pma1 to the PM and a rerouting of Pma1 to vacuoles in a manner dependent on the trans-Golgi network (TGN) to late endosome (LE) trafficking pathway. Since the TGN-LE pathway controls endosomal and vacuolar TORC1, it may be the anti-aging pathway boosted by up-regulated Osh6.