By Samantha Black, Ph.D.

October 25, 2019 -- A new study published in Nature Communications on October 25 provides evidence of how microproteins contribute to cellular stress. Researchers from Salk Institute suggest that these small proteins can cause dysregulation, which underlies several debilitating diseases including cancer, neurodegenerative disorders, and diabetes.

Microproteins are classified as peptides that contain fewer than 100 amino acids and are translated from small open reading frames. Mammalian genomes have hundreds to thousands of these previously unannotated microproteins. The study of these peptides could lead scientists to gain new insights into biology.

In the current study, researchers identify a microprotein, phosphatidylinositol glycan anchor biosynthesis class B (PIGB) opposite stand 1 (PIGBOS), that is implicated in the unfolded protein response (UPR) which triggers the onset of endoplasmic reticulum (ER) stress caused by the accumulation of unfolded proteins in the lumen.

"This study is exciting because cell stress is important in a number of different diseases, including cancer and neurodegeneration," says Salk Professor Alan Saghatelian, co-corresponding author of the study. "By understanding the mechanisms behind these diseases, we think we'll have a better shot at treating them."

PIGBO is a tryptic peptide in the human genome which contains 54 amino acids. The transcript consists of two exons and three splice isoforms. The researchers used RNA-seq and ribosome profiling to confirm the presence of PIGBO is human cell lines. To further confirm that a stable microprotein was formed, the researchers used western blot analysis.

The study showed that PGBOS is a mitochondrial outer membrane protein which interacts with the ER. Through a series of knockout and CRISPR experiments, the team was able to show that modulating PIGBOS can modulate cellular sensitivity towards ER stress, which in turn increases apoptosis and the ability of cells to survive stress.

"PIGBOS is like a connection to link mitochondria and ER together," says Chu. "We hadn't seen that before in microproteins--and it's rare in just normal proteins."

Using split green fluorescent protein (GFP) tagging, the team determined that PIGBOS communicates with CLCC1, a chloride channel protein found on the ER membrane, to regulate stress in the ER. In the absence of PIGBOS, UPR is upregulated and may cause a buildup of misshapen proteins.

"Going forward, we might consider how PIGBOS is involved in disease like cancer," says Qian Chu, postdoctoral researcher at Salk Institutes. "In cancer patients, the ER is more stressed than in a normal person, so ER stress regulation could be a good target."


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