An international consortium of scientists has published a groundbreaking study in the journal Nature, revealing a 'consensus landscape' of the human microproteome and identifying thousands of previously hidden microproteins.
Among the global experts of the TransCODE Consortium was Hudson Institute's Associate Professor Pouya Faridi, the sole Australian researcher to contribute to this significant scientific milestone.
A/Prof Faridi is Head of the Translational Antigen Discovery Laboratory at Hudson Institute of Medical Research, and Director of the Clinical Proteomics Facility in the Department of Medicine, School of Clinical Sciences at Monash Health.
Shining a light on the microproteome
This study addresses a fundamental question in biology: what has been missed in previous analyses of the human protein-coding genome?
For decades, scientific investigation has focused on the approximately 19,500 known 'canonical' protein-coding genes – the standard, widely recognized, and biologically active DNA sequences that serve as templates for creating the primary proteins essential for cellular function. However, there is also a collection of microproteins, termed the microproteome – very short sequences that, despite their small size, serve important functions in biology.
"Dark proteome" filled with hidden proteins
This new research shines a light on the "dark proteome", a vast array of small microproteins translated from non-canonical open reading frames (ncORFs) that have historically been overlooked because they are so small.
Taking 'a big data' approach, the researchers analysed outputs from over 95,000 immunopeptidomics and proteomics experiments and billions of mass spectrometry datapoints from publicly-available databases, searching for signals of extremely small proteins. In doing so, they found strong evidence for over 1,700 previously unknown proteins. They've dubbed these tiny molecules "peptideins": a new class of microproteins made by the body, but whose roles so far remain largely a mystery.
Their findings carry major clinical implications, as microproteins are known to play a role in diseases such as cancer – raising the possibility that these peptideins could serve as promising targets for developing future new therapies.
A/Prof Faridi's involvement highlights Australia's world-class standing in immunopeptidomics and antigen discovery.
As the only Australian author in the consortium, he worked alongside researchers from leading global institutions, such as Institute for Systems Biology, Oncode Institute, University of Michigan, Massachusetts Institute of Technology, Harvard University and the European Molecular Biology Laboratory (EMBL), to establish standardised guidelines for how these new proteins should be catalogued for future medical research.
"Hidden layer of biology" offers opportunities for targeted treatments
A/Prof Faridi said the study shows that scientists have previously only seen part of the picture. "There is a hidden layer of proteins that the immune system can already detect, but that we weren't aware of until now. This gives us entirely new opportunities to develop targeted treatments, particularly in cancer," he said.
"By uncovering this hidden layer of biology, we can start to design therapies that are more precise and effective. This work also highlights the power of combining technologies like immunopeptidomics, ribosome sequencing and genomics to reveal new fundamental aspects of biology. "It's an exciting step forward for both basic science and clinical translation, as by defining these new components of the human proteome, the study provides a vital roadmap for future treatment development and biomedical discovery."
