Regulation of the ER stress response by a mitochondrial microprotein

Nat Commun. 2019 Oct 25;10(1):4883. doi: 10.1038/s41467-019-12816-z.


Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER-mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an undiscovered role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Death
  • Cell Line, Tumor
  • Chloride Channels / metabolism*
  • Chlorocebus aethiops
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / metabolism*
  • Protein Interaction Maps
  • Rabbits
  • Rats
  • Unfolded Protein Response*


  • CLCC1 protein, human
  • Chloride Channels
  • Mitochondrial Proteins
  • PIGBOS1 protein, human