The Ubiquitination of RIPK2 is Mediated by Peli3 and Negatively Regulates the Onset of Infectious Osteomyelitis.

Abstract

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