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

Regulation of the ER stress response by a mitochondrial microprotein.

Author information

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. umanor@salk.edu.
4
The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology, 10010N. Torrey Pines Rd, La Jolla, CA, 92037, USA. asaghatelian@salk.edu.

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.

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