UC Irvine

Cellular homeostasis relies on a dedicated and coordinated response to a variety of stresses. In the endoplasmic reticulum (ER) the accumulation of unfolded proteins triggers the unfolded protein response (UPR), a conserved stress response aimed at mitigating damage and returning cells to homeostasis. Dysregulation of UPR underlies many 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. Support or Funding Information: This research was supported by NIH/NIGMS (R01GM102491, A.S.), the Leona M. and Harry B. Helmsley Charitable Trust grant (A.S.), Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals (A.S.), the George E. Hewitt Foundation for medical research (Q.C.), the Anderson Foundation (Q.C.), NIH F32 fellowship (GM123685, T.F.M.) and the Pioneer Fellowship(D.T.). Imaging work was supported by the Waitt Advanced Biophotonics Core Facility of the Salk Institute with funding from NIH‐NCI CCSG: P30 014195, NINDS Neuroscience Core Grant: NS072031 and the Waitt Foundation. Proteomics studies were supported by the Mass Spectrometry Core of the Salk Institute with funding from the NIH with an NCI Cancer Center Support Grant P30 (CA014195).