mTORC1 regulates GRASP55-dependent unconventional secretion in response to stress

In cells, several cargoes are delivered to the cell surface or the extracellular space via unconventional secretion routes. GRASP55 is a Golgi protein that regulates unconventional secretion of distinct proteins and controls the assembly and membrane stacking of Golgi cisternae. Recent work suggested that the role of GRASP55 in unconventional secretion may involve its relocalization to other organelles. However, the stimuli that drive GRASP55-dependent unconventional secretion, the signaling events that regulate GRASP55 function, the subcellular locations where GRASP55 acts, and the cargoes that follow this route for secretion remain unclear. Here, we show that mTORC1 directly phosphorylates GRASP55 at multiple sites to maintain its Golgi localization. Cellular stresses or drugs that inhibit mTORC1 cause GRASP55 dephosphorylation and relocalization to autophagosomal / MVB structures. Using secretome and surfactome analyses in GRASP55-null cells, we identify for the first time numerous -previously unknown- cargoes that rely on this unconventional secretory pathway.