An mTORC1-GRASP55 signaling axis controls unconventional secretion to reshape the extracellular proteome upon stress

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.

Keywords: ECM; GORASP2; GRASP55; Golgi; MMP2; Rapamycin; Tuberous Sclerosis Complex (TSC); cellular stress response; mTORC1; unconventional protein secretion (UPS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Extracellular Matrix / genetics
  • Golgi Apparatus / genetics
  • Golgi Matrix Proteins / genetics*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Membrane Proteins / genetics
  • Protein Transport / genetics
  • Proteome / genetics*
  • Proteomics*
  • Signal Transduction / genetics
  • Stress, Physiological / genetics*


  • GORASP2 protein, human
  • Golgi Matrix Proteins
  • Membrane Proteins
  • Proteome
  • Mechanistic Target of Rapamycin Complex 1