InteractORF, predictions of human sORF functions from an interactome study

Short Open Reading Frames (sORFs) are ubiquitous genomic elements that have been overlooked for years, essentially due to their short length (< 100 residues) and the use of alternative start codons (other than AUG). However, some may encode functional peptides, so-called sORF-encoded peptides (sPEPs), whose functions remain mainly unknown. In this study, we propose a system approach to determine the functions of sPEPs in monocytes. We first predicted the interactions of sPEPs with canonical proteins and analyzed the interfaces of interactions as well as the set of canonical proteins interacting with sPEPs. Second, by joining these sPEP-canonical protein interactions with the human interactome, we predicted the first sPEP interactome network to date. Based on its topology, we then predicted the function of the sPEPs. Our results suggest that the majority of sPEPs are involved in key biological functions, including regulatory functions, metabolism, and signaling. Overall, the diversity in the predicted functions of the sPEPs underlines the prevalence of their role in different biological mechanisms, suggesting that they are major regulatory actors.