Cancer cells overcome stress with new microprotein uncovered by scientists at SciLifeLab
The researchers have tested more than 11,000 potential microproteins to identify which affect cell survival during stress, something that could lead to new therapies.
Researchers in the Elsässer, Piazza and Lehtiö labs at SciLifeLab and Karolinska Institutet have developed powerful screening methods to uncover the hidden roles of tiny proteins, so-called microproteins, that have remained largely mysterious until now.
”This project is a good demonstration that SciLifeLab is not only about cutting-edge technologies under one roof, but also pushing the field by curiosity driven experts interacting to make use of the technologies. Here, we could harness our novel proteogenomics toolkit to discover new biology with Simon’s and Ilaria’s teams,” says Janne Lehtiö, Group Leader at SciLifeLab and Karolinska Institutet, and Scientific Lead for Precision Medicine at SciLifeLab.
These miniature proteins are smaller than proteins such as Ubiquitin, which is traditionally considered at the lower size end of human proteins. Miniature proteins are increasingly recognized as important players in how our cells function, but elucidating their function at scale has been a major challenge.
“The identification and characterization of PIPPI posed a major challenge for us, since it appears to be produced from a highly duplicated chromosomal region of the human genome,” says Simon Elsässer, Group Leader at SciLifeLab and Karolinska Institutet, and the study’s last author. “The NPIPI gene cluster has attracted much attention from geneticists due to its rapid evolution in the hominid lineage, but its functional role in human biology and disease remains mysterious.”
Thousands of proteins at once
In the study published in the journal Nucleic Acids Research, the team used a large-scale screening approach to test more than 11,000 potential microproteins at once. By doing so, they were able to identify which of these small molecules have a measurable impact on cell survival under stress.
“This was our first experience studying microproteins, a fascinating but technically challenging area. Microproteins are tiny, often overlooked pieces of the proteome, and detecting or characterizing them pushes the limits of current proteomic tools. It was exciting to see how a systematic screening approach could actually uncover a new functional microprotein like PIPPI, revealing its role in cellular stress responses,” says Ilaria Piazza, Group Leader at SciLifeLab, Stockholm University and Karolinska Institutet. “We’re now interested in discovering other examples of microproteins with Simon and other groups at SciLifeLab”.
One of the discovered microproteins, named PIPPI after its genomic source region, the NPIP gene cluster, was found to protect cells from stress in the endoplasmic reticulum — a compartment in the cell that helps fold and process predominantly secreted and membrane proteins. The researchers showed that PIPPI interacts with key proteins in this stress-response pathway, helping cells maintain balance when challenged.
“Our approach allows us to systematically identify functional microproteins and understand their roles in cellular processes,” says Simon Elsässer. “Microproteins like PIPPI may turn out to be important regulators of how cells respond to stress, and could offer new clues for understanding disease mechanisms”.
The findings open up many questions for further research. Because cell stress and protein misfolding are involved in many diseases, including cancer and neurodegenerative disorders, insights into how microproteins influence these processes could one day contribute to new therapeutic strategies.
DOI: 10.1093/nar/gkaf1072
