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.
Qian Chu  1 ,  Thomas F Martinez  1 ,  Sammy Weiser Novak  2 ,  Cynthia J Donaldson  1 ,  Dan Tan  1 ,  Joan M Vaughan  1 ,  Tina Chang  1 ,  Jolene K Diedrich  1 ,  Leo Andrade  2 ,  Andrew Kim  1 ,  Tong Zhang  2 ,  Uri Manor  3 ,  Alan Saghatelian  4
Affiliations
  • 1. The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology, 10010N. Torrey Pines Rd, La Jolla, CA, 92037, USA.
  • 2. The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center, 10010N. Torrey Pines Rd, La Jolla, CA, 92037, USA.
  • 3. The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center, 10010N. Torrey Pines Rd, La Jolla, CA, 92037, USA. [email protected].
  • 4. The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology, 10010N. Torrey Pines Rd, La Jolla, CA, 92037, USA. [email protected].
PMID: 31653868 DOI: 10.1038/s41467-019-12816-z
Abstract

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.