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.
Highlights
Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses
During proteomic searches for microproteins, we identified a tryptic peptide, MQLVQESEEK, from the human 54-amino acid phosphatidylinositol glycan anchor biosynthesis class B (PIGB) opposite strand 1 (PIGBOS) microprotein (Fig. 1a), providing experimental evidence for PIGBOS translation
The PIGBOS transcript consists of two exons and has three splice isoforms with slight differences in the first exon, but the second exon that contains the entire PIGBOS small open reading frames (smORFs) is the same (Supplementary Fig. 1a)
Summary
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. 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. There are three primary branches of the UPR pathway and each pathway is mediated by a different ER protein: IRE1, PERK, or ATF611 Activation of these proteins during UPR initiates signals at the ER that slow down protein expression, increase protein folding, and upregulate degradation of unfolded proteins[9,10]. We characterize a microprotein called PIGBOS and reveal a role for a mitochondrial protein in UPR signaling
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