The ubiquitination of RIPK2 is mediated by Peli3 and negatively regulates the onset of infectious osteomyelitis.

Osteomyelitis is the infection and destruction of bone. Until now, there is no universal protocol for its treatment. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was implicated in the development of osteomyelitis. However, its detailed mechanism remains unknown. 6-8 weeks old wild-type or Pellino E3 Ubiquitin Protein Ligase Family Member 3 (Peli3) deficiency mice were injected with S. aureus to induce osteomyelitis. RAW264.7 cells or bone marrow-derived macrophages (BMDMs) isolated from mice, were treated with lipopolysaccharides (LPS). Knocking down Peli3 in RAW264.7 cells increased the expressions of inflammatory cytokines after the stimulation of LPS, including interleukin-1β, interleukin-6 and tumor necrosis factor-α. Inflammation was also activated in S. aureus-induced Peli3 deficiency mice. Moreover, Peli3 deficiency mice also displayed more severe symptoms of osteomyelitis in S. aureus-infected mice. Moreover, Peli3 targeted and degraded RIPK2 through K48-linked ubiquitination. Peli3 negatively modulates osteomyelitis by degrading RIPK2. Our data further expand current understanding of RIPK2 on osteomyelitis, which suggests that RIPK2 might serve as novel therapeutic target for treating osteomyelitis.