Max Planck Institute for Biology of Ageing (MPI-AGE), 50931 Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Biochemistry, 50931 Cologne, Germany.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Biochemistry, 50931 Cologne, Germany.
Mol Cell. 2021 Aug 19;81(16):3275-3293.e12. doi: 10.1016/j.molcel.2021.06.017. Epub 2021 Jul 9.
Cells communicate with their environment via surface proteins and secreted factors. Unconventional protein secretion (UPS) is an evolutionarily conserved process, via which distinct cargo proteins are secreted upon stress. Most UPS types depend upon the Golgi-associated GRASP55 protein. However, its regulation and biological role remain poorly understood. Here, we show that the mechanistic target of rapamycin complex 1 (mTORC1) directly phosphorylates GRASP55 to maintain its Golgi localization, thus revealing a physiological role for mTORC1 at this organelle. Stimuli that inhibit mTORC1 cause GRASP55 dephosphorylation and relocalization to UPS compartments. Through multiple, unbiased, proteomic analyses, we identify numerous cargoes that follow this unconventional secretory route to reshape 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.
细胞通过表面蛋白和分泌因子与环境进行通讯。非典型蛋白分泌（UPS）是一种进化上保守的过程，通过该过程，不同的货物蛋白在应激时被分泌。大多数 UPS 类型依赖于高尔基相关 GRASP55 蛋白。然而，其调控和生物学功能仍知之甚少。在这里，我们表明，雷帕霉素复合物 1（mTORC1）直接磷酸化 GRASP55 以维持其高尔基体定位，从而揭示了 mTORC1 在该细胞器中的生理作用。抑制 mTORC1 的刺激导致 GRASP55 去磷酸化并重新定位到 UPS 隔室。通过多种非偏见的蛋白质组学分析，我们鉴定了许多遵循这种非典型分泌途径的货物，以重塑细胞分泌组和表面组。使用 MMP2 分泌作为 UPS 的替代物，我们提供了对其调控和生理作用的重要见解。总的来说，我们的发现揭示了 mTORC1-GRASP55 信号枢纽作为 UPS 上游应激信号的整合点，以及细胞应激适应的关键协调器。
