Microprotein Plays Key Role in Modulating UPR in Response to ER Stress

In recent years, it has become clear that small (< 20kD), single-domain proteins known as microproteins play important roles in a diversity of biological processes such as DNA repair, muscle development, and even in the maintenance of the human microbiome. However, while rich in research potential, this scientific field remains woefully understudied. Researchers at the Salk Institute are trying to change that, and have uncovered a novel mitochondrial microprotein that plays a key role in regulating the unfolded protein response (UPR).

Unfolded protein response, ER stress, microprotein, mitochondria

Live cell image of mitochondria (red) in COS-7 cells shows that PIGBOS (green) is localized to the mitochondrial outer membrane (orange).*

In a study published in Nature Communications, Chu et al. identified PIGBOS, a small, conserved 54-amino acid microprotein, located on the mitochondrial outer membrane. The researchers found that PIGBOS interacted specifically with CLCC1, a chloride channel protein located on the endoplasmic reticulum. Using a split-GFP bimolecular complementation approach, the researchers fluorescently visualized the PIGBOS-CLCC1 interaction at the ER-mitochondria interface, and quantified the interaction using flow cytometry. Seeing as CLCC1 has previously been associated with neurodegeneration in a mice, and that this disease phenotype is tied to an increase in UPR, the researchers next evaluated whether PIGBOS was associated with UPR. As hypothesized, they showed that PIGBOS levels can indeed regulate UPR. In PIGBOS knockout cells and in cells treated with PIGBOS siRNA, an increase in XBP1 splicing in response to tunicamycin treatment was observed. Tunicamycin is known to trigger ER stress, and XBP1 splicing is a reliable indicator of UPR. Conversely, PIGBOS overexpression in wildtype cells were desensitized to UPR. Furthermore, the research group was also able to show that PIGBOS could regulate cellular apoptosis, where the loss of PIGBOS resulted in greater sensitivity to ER stress, resulting in increased cell death.

Dysregulation of protein folding underlies many neurodegenerative disorders in humans like Alzheimer’s and Parkinson’s disease. Better understanding into the role mitochondria play in regulating the ER stress response will certainly aid in future therapeutic development. It is also clear that functional microproteins bear great importance to the biological processes. With so much potential for discovery, it is exciting to see where the field of microprotein research will take us next.

  • Chu, Q., Martinez, T.F., Novak, S.W. et al. Regulation of the ER stress response by a mitochondrial microprotein. Nat Commun 10, 4883 (2019) doi:10.1038/s41467-019-12816-z

*This unmodified image corresponds to Figure 2D from Chu et al. (2019), and is gratefully shared under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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