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

eLife

Gabriel Mbalaviele¹  Manoj Arra²  Ke Ke²  Gaurav Swarnkar²  Jie Shen²  Naga Suresh Adapala²  Yousef Abu-Amer³ 

[1] Bone and Mineral Division, Department of Medicine, Washington University School of Medicine, St. Louis, United States;Department of Orthopaedic Surgery and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, United States;Department of Orthopaedic Surgery and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, United States;Shriners Hospital for Children, St. Louis, United States;

关键词: nk-kb;    NEMO;    osteoclast;    ISG15;    RANKL;    osteolysis;    Mouse;   

DOI  :  10.7554/eLife.56095

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY