The Dark Proteome: a network of stealthy proteins interacting with cellular systems and implicated in human disease

Growing experimental evidence demonstrates that proteins encoded by noncanonical open reading frames (ORFs) play important functional and physiological roles. Many of these proteins belong to the so-called “dark proteome” the portion of the proteome that remains poorly characterized despite advances in genomics and proteomics. Among these are microproteins, typically defined as proteins comprising fewer than 100 amino acids, which are increasingly recognized as biologically active regulators of diverse cellular processes.Although thousands of putative microproteins have been predicted across the human genome, the vast majority remain uncharacterized, and they are generally under-represented in the enormous body of proteomics-based scientific data to date. Consequently, the true protein-coding capacity of the human genome is still not fully understood. The discovery of microproteins encoded by long noncoding RNAs (lncRNAs), untranslated regions (UTRs), alternative reading frames, and other noncanonical genomic regions has challenged traditional views of gene annotation and expanded our understanding of the coding landscape.Microproteins are often characterized by compact structures and specialized functions, enabling them to regulate molecular pathways through interactions with larger protein complexes, nucleic acids, or signaling networks. Emerging studies have implicated microproteins in diverse biological processes, including gene regulation, cell proliferation, metabolism, development, and immune responses, as well as in the pathogenesis of cancer, neurological disorders, cardiovascular disease, and other human diseases.Despite their growing significance, the identification and characterization of microproteins remain technically challenging. Their small size limits the number of detectable peptides generated for mass spectrometry (MS)-based analyses, while many microproteins are expressed at low abundance and exhibit rapid turnover. Nevertheless, recent technological advances, including ribosome profiling, long-read sequencing, single-cell omics, proteogenomics, targeted proteomics, structural biology approaches, and artificial intelligence (AI)-driven computational methods are transforming the discovery and functional investigation of these elusive proteins.As the field continues to mature, microproteins are emerging as promising biomarkers, therapeutic targets, and previously unrecognized regulators of cellular physiology. Improved understanding of their structure, function, evolutionary origins, and disease associations will provide important insights into the dark proteome and may reveal novel opportunities for precision medicine.This Research Topic aims to highlight recent advances in microprotein biology and foster discussion on emerging concepts, technologies, and applications that are shaping this rapidly evolving field.Themes of interest include, but are not limited to:• Emerging roles for microproteins in disease• Mutations and genetic variation in newly discovered microproteins• Experimental validation and functional characterization of microproteins• Novel technologies and computational tools for microprotein discovery and analysis• Microproteins: discovery, evolution, structure, and function• Noncanonical ORFs and the dark proteome• Proteogenomic approaches for identifying translated small ORFs• Microproteins as biomarkers and therapeutic targets• AI and machine learning applications in microprotein research• Microproteins in precision medicine and translational research Topic editors: Paul Dowling, Cristina Maracci Source: https://www.frontiersin.org/research-topics/82492/the-dark-proteome-a-network-of-stealthy-proteins-interacting-with-cellular-systems-and-implicated-in-human-disease