Regulation of the ER stress response by a mitochondrial microprotein

Qian Chu, Thomas F. Martinez, Sammy Weiser Novak, Cynthia J. Donaldson, Dan Tan, Joan M. Vaughan, Tina Chang, Jolene K. Diedrich, Leo Andrade, Andrew Kim, Tong Zhang, Uri Manor () and Alan Saghatelian ()
Additional contact information
Qian Chu: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology
Thomas F. Martinez: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology
Sammy Weiser Novak: The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center
Cynthia J. Donaldson: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology
Dan Tan: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology
Joan M. Vaughan: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology
Tina Chang: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology
Jolene K. Diedrich: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology
Leo Andrade: The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center
Andrew Kim: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology
Tong Zhang: The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center
Uri Manor: The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center
Alan Saghatelian: The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12816-z

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