Auto-regulation of Secretory Flux by Sensing and Responding to the Folded Cargo Protein Load in the Endoplasmic Reticulum

Cell. 2019 Mar 7;176(6):1461-1476.e23. doi: 10.1016/j.cell.2019.01.035.


Maintaining the optimal performance of cell processes and organelles is the task of auto-regulatory systems. Here we describe an auto-regulatory device that helps to maintain homeostasis of the endoplasmic reticulum (ER) by adjusting the secretory flux to the cargo load. The cargo-recruiting subunit of the coatomer protein II (COPII) coat, Sec24, doubles as a sensor of folded cargo and, upon cargo binding, acts as a guanine nucleotide exchange factor to activate the signaling protein Gα12 at the ER exit sites (ERESs). This step, in turn, activates a complex signaling network that activates and coordinates the ER export machinery and attenuates proteins synthesis, thus preventing large fluctuations of folded and potentially active cargo that could be harmful to the cell or the organism. We call this mechanism AREX (autoregulation of ER export) and expect that its identification will aid our understanding of human physiology and diseases that develop from secretory dysfunction.

Keywords: AKAP; COPII; ER exit sites; ER export; PKA; auto-regulatory systems; folded cargo; homeostasis; membrane traffic; signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • COP-Coated Vesicles / metabolism
  • COP-Coated Vesicles / physiology
  • Cell Line
  • Coatomer Protein / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / physiology
  • Endoplasmic Reticulum Stress / physiology
  • Female
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • Golgi Apparatus / metabolism
  • Guanine Nucleotide Exchange Factors / physiology
  • HeLa Cells
  • Humans
  • Male
  • Protein Folding
  • Protein Transport
  • Proteostasis / physiology
  • Signal Transduction
  • Vesicular Transport Proteins / metabolism*


  • Coatomer Protein
  • Guanine Nucleotide Exchange Factors
  • SEC24A protein, human
  • Vesicular Transport Proteins
  • GTP-Binding Protein alpha Subunits, G12-G13