PIGBOS Microprotein Has Role in Regulating Unfolded Protein Response

The importance of microproteins is coming to the fore as a result of genomic and proteomics advances. These small proteins (with fewer than 100 amino acids) appear to be key to some cellular processes. A study published today in Nature Communications delves into PIGBOS, a 54-amino acid microprotein that researchers at the Salk Institute say contributes to mitigating endoplasmic reticulum stress response.

"This study is exciting because cell stress is important in a number of different diseases, including cancer and neurodegeneration," says Alan Saghatelian, co-corresponding author of the study.

The study began when Salk postdoctoral researcher and first author Qian Chu detected PIGBOS in mitochondria and wondered what its role could be. The team reached out to co-corresponding author Uri Manor, director of the Waitt Advanced Biophotonics Core Facility at Salk, for help. At first, Manor was unable to attach a green florescent protein (GFP) to PIGBOS. The microprotein was just too small relative to the size of GFP. Manor's team finally solved this problem by using split GFP, where they fused just a small part of GFP to PIGBOS.

When the researchers could finally see PIGBOS and started to map its location, they realized that it sits on the outer membrane of the mitochondria, poised to make contact with proteins on other organelles. They were surprised to see PIGBOS interacting with CLCC1, a protein that is part of the endoplasmic reticulum (ER).

The researchers found that PIGBOS communicates with CLCC1 to regulate stress in the ER. Without PIGBOS, the ER is more likely to experience stress, which leads to a chain of events where the cell tries to clear out harmful misshapen proteins (the unfolded protein response). If the cell fails to dispose of these proteins, it will initiate a self-destruct sequence and die. The scientists were not expecting to see a role for a mitochondrial protein in the unfolded protein response. This new understanding of PIGBOS opens the door to future therapies that can target cell stress, according to the Salk team.