Inflammatory osteolysis is regulated by site-specific ISGylation of the scaffold protein NEMO

Naga Suresh Adapala, Gaurav Swarnkar, Manoj Arra, Jie Shen, Gabriel Mbalaviele, Ke Ke, Yousef Abu-Amer

Research output: Contribution to journalArticle

Abstract

Inflammatory osteolysis is governed by exacerbated osteoclastogenesis. Ample evidence points to central role of NF-κB in such pathologic responses, yet the precise mechanisms underpinning specificity of these responses remain unclear. We propose that motifs of the scaffold protein IKKγ/NEMO partly facilitate such functions. As proof-of-principle, we used site-specific mutagenesis to examine the role of NEMO in mediating RANKL-induced signaling in mouse bone marrow macrophages, known as osteoclast precursors. We identified lysine (K)270 as a target regulating RANKL signaling as K270A substitution results in exuberant osteoclastogenesis in vitro and murine inflammatory osteolysis in vivo. Mechanistically, we discovered that K270A mutation disrupts autophagy, stabilizes NEMO, and elevates inflammatory burden. Specifically, K270A directly or indirectly hinders binding of NEMO to ISG15, a ubiquitin-like protein, which we show targets the modified proteins to autophagy-mediated lysosomal degradation. Taken together, our findings suggest that NEMO serves as a toolkit to fine-tune specific signals in physiologic and pathologic conditions.

Original languageEnglish (US)
Article numbere56095
JournaleLife
Volume9
DOIs
StatePublished - Mar 2020
Externally publishedYes

Keywords

  • IKKγ
  • ISG15
  • NEMO
  • NF-κB
  • Osteoclast
  • Osteolysis
  • RANKL

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Adapala, N. S., Swarnkar, G., Arra, M., Shen, J., Mbalaviele, G., Ke, K., & Abu-Amer, Y. (2020). Inflammatory osteolysis is regulated by site-specific ISGylation of the scaffold protein NEMO. eLife, 9, [e56095]. https://doi.org/10.7554/eLife.56095