OPN-Derived Peptides Generated by Proteasomes Can Promote Cell Migration via CD44 Activation

Osteopontin (OPN) is a pleiotropic cytokine that is overexpressed in many autoimmune diseases and solid cancers. Here we show that the 20S proteasome can degrade, in vitro, both the full-length OPN and the OPN-C fragment generated in the extracellular space and produce both canonical and spliced peptides. Specific canonical OPN-derived peptides, generated from hotspots within the OPN sequences, can regulate cell migration via CD44. By predicting peptide-protein docking, we propose that this could occur by displacing the flexible C-terminal region from the CD44 α1 helix, promoting a conformational change in CD44 that could lead to the activation of downstream signalling pathways. We also identify key amino acid residues within these OPN-derived peptides that impact the activation of CD44 to initiate cell migration and predict their binding to the CD44 asparagine 164 residue-previously implicated in stabilising the CD44 structure to promote cell migration. Therefore, we propose that proteasomes can process various OPN isoforms, theoretically both inside and outside a cell, leading to the presence of OPN-derived peptides in the extracellular space where they can play an immunological role. This process, which others showed to represent an antibacterial defence, could also be involved in the regulation of cell surface receptors.