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

Lixiang Le1, Haojie Shan2, Yiwei Lin2

  • 1Department of Orthopedic Surgery, the Second Affiliated Hospital of Soochow University, China.

Japanese Journal of Infectious Diseases
|April 30, 2023
PubMed

Insights

Pellino E3 Ubiquitin Protein Ligase Family Member 3 (Peli3) deficiency exacerbates osteomyelitis by increasing inflammation. Peli3 degrades Receptor-interacting serine/threonine-protein kinase 2 (RIPK2), suggesting RIPK2 as a therapeutic target for bone infection.

Area of Science:

  • Immunology
  • Molecular Biology
  • Orthopedics

Background:

  • Osteomyelitis, a severe bone infection, lacks a universal treatment protocol.
  • Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is implicated in osteomyelitis, but its mechanism is unclear.
  • Pellino E3 Ubiquitin Protein Ligase Family Member 3 (Peli3) role in osteomyelitis is not well-defined.

Purpose of the Study:

  • To elucidate the role of Peli3 in osteomyelitis pathogenesis.
  • To investigate the interaction between Peli3 and RIPK2 in the context of bone infection.
  • To explore potential therapeutic targets for osteomyelitis.

Main Methods:

  • Induction of osteomyelitis in wild-type and Peli3-deficient mice using Staphylococcus aureus.
  • Stimulation of RAW264.7 cells and bone marrow-derived macrophages with lipopolysaccharide (LPS).
  • Assessment of inflammatory cytokine expression and osteomyelitis severity.
  • Analysis of Peli3-mediated degradation of RIPK2 via ubiquitination.

Main Results:

  • Peli3 knockdown in macrophages increased inflammatory cytokine expression (IL-1β, IL-6, TNF-α) upon LPS stimulation.
  • Peli3-deficient mice exhibited heightened inflammation and more severe osteomyelitis symptoms after S. aureus infection.
  • Peli3 was found to target and degrade RIPK2 through K48-linked ubiquitination.
  • Peli3 negatively modulates osteomyelitis by degrading RIPK2.

Conclusions:

  • Peli3 plays a protective role in osteomyelitis by degrading RIPK2.
  • RIPK2 signaling contributes to osteomyelitis severity.
  • Targeting RIPK2 may offer a novel therapeutic strategy for treating osteomyelitis.
Keywords:
K48-linked ubiquitinationPeli3RIPK2inflammationosteomyelitis

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