A novel mTORC1-GRASP55 signaling axis reshapes the extracellular proteome upon stress. Nüchel et al.
Description
Cells communicate with their environment via surface proteins and secreted factors. However, how environmental cues modify the extracellular proteome is not known. Unconventional protein secretion (UPS) is an evolutionarily conserved process, via which proteins reach the cell surface or the extracellular space upon stress. The Golgi-associated GRASP55 protein facilitates unconventional secretion of distinct cargo proteins. Notably, despite the emerging importance of UPS for human disease, its regulation and biological role remain poorly understood. Here, we identify mTORC1 as the first signaling pathway controlling UPS. Mechanistically, mTORC1 phosphorylates GRASP55 directly to retain its Golgi localization, thus revealing a physiological role for mTORC1 at the Golgi. Stimuli that inhibit mTORC1 cause GRASP55 dephosphorylation and relocalization to UPS compartments. Through multiple unbiased proteomic analyses, we comprehensively characterize numerous cargoes that follow this unconventional secretory route to shape the cellular secretome and surfactome. Using MMP2 secretion as a proxy for UPS, we provide important insights on its regulation and physiological role. Collectively, our findings reveal the mTORC1-GRASP55 signaling hub as the integration point in stress signaling upstream of UPS, and as a key coordinator of the cellular adaptation to stress.