Streptococcal Mannose Phosphotransferase System Component IID Is a Novel RANK‐Binding Osteoclastogenic Factor

Streptococci, Gram-positive opportunistic pathogens, can cause inflammatory bone diseases, yet their virulence factors remain unclear. We investigated streptococcal components contributing to bone pathology. Unlike Staphylococcus aureus, streptococci and lipoprotein-deficient strains induced comparable bone destruction and osteoclastogenesis in mice via a TLR2-independent pathway. A comparative Q Exactive Plus mass spectrometric analysis of streptococcal and staphylococcal membrane proteins led us to identify mannose phosphotransferase system component IID (Man-PTSIID) as a novel osteoclastogenic factor. Recombinant Man-PTSIID and synthetic peptides containing conserved amino acid sequences of Man-PTSIIDs found in various streptococci bound to the receptor activator of nuclear factor-κB (RANK), as demonstrated by an SPR analysis. Structural modeling and molecular docking analysis, together with full-length Man-PTSIID binding assays, demonstrated an interaction between Man-PTSIID and RANK. Streptococcal Man - PTSIID promotes terminal osteoclast maturation and multinucleation following RANKL priming via the RANK signaling pathway, rather than mimicking native RANKL or functioning as an independent RANK agonist. Consistently, the osteoclastogenic effects induced by streptococci were not observed in Man-PTSIID-deficient mutant strains. Collectively, these findings suggest that Man-PTSIID is a novel, differentiation stage-dependent osteoclastogenic factor contributing to terminal osteoclast differentiation and plays a critical role in bone pathology during streptococcal infections.