• DOI:10.1038/nri3455
• Corpus ID: 35608265

Signalling: Fine-tuning of inflammation by F-box proteins

@article{Bordon2013SignallingFO,
  title={Signalling: Fine-tuning of inflammation by F-box proteins},
  author={Yvonne Bordon},
  journal={Nature Reviews Immunology},
  year={2013},
  volume={13},
  pages={304-305}
}

• Yvonne Bordon
• Published 25 April 2013
• Biology
• Nature Reviews Immunology

(TRAFs) are crucial adaptor proteins that link membrane-bound immune receptors (including tumour necrosis factor (TNF) receptors and Toll-like receptors) to downstream signalling cascades. Chen et al. now report that F-box and leucine-rich repeat protein 2 (FBXL2) and F-box only protein 3 (FBXO3) fine-tune pro-inflammatory cytokine production by regulating the stability of TRAFs. F-box proteins contribute to ubiquitin-mediated responses by providing substrate specificity to the SKP1–CUL1–F-box protein (SCF) superfamily of E3 ligases. The authors sought to identify the substrates that were targeted by FBXL2. They found that FBXL2 interacted with and lowered the expression of TRAF1– TRAF6 in a mouse lung epithelial cell line. When expression of FBXL2 was knocked down in a macrophage cell line (U937), the cells showed increased levels of TRAF proteins and produced greater amounts of pro-inflammatory cytokines following exposure to lipopolysaccharide (LPS). This suggests that FBXL2 can inhibit pro-inflammatory cytokine responses by targeting TRAFs for cellular degradation. Next, the authors examined how FBXL2 itself is regulated. They found that FBXL2 is phosphorylated by glycogen synthase kinase 3β and that FBXO3 promotes the ubiquitylation and degradation of phosphorylated FBXL2. In keeping with this observation, knockdown of FBXO3 increased the half-life of FBXL2 and decreased the levels of TRAF1– TRAF6 in cell lines. Interestingly, the authors identified a naturally occurring FBXO3 polymorphism in individuals of European descent. Compared with blood cells from individuals who were homozygous for wild-type FBXO3, blood cells from individuals who were heterozygous for the variant FBXO3 showed lower pro-inflammatory cytokine production following stimulation with LPS. Closer analysis showed that SCF complexes that incorporate the variant FBXO3 have an impaired ability to polyubiquitylate FBXL2. Furthermore, overexpression of wild-type FBXO3 in U937 cells decreased intracellular FBXL2 levels and increased levels of TRAF1–TRAF6. So, FBXO3 can increase pro-inflammatory cytokine production by targeting FBXL2 for degradation, thereby preventing FBXL2-mediated suppression of TRAFs. The authors explored how this regulatory mechanism affects inflammation in vivo. In a mouse model of Pseudomonas aeruginosa-induced lung injury, FBXO3 promoted proinflammatory cytokine production and cellular infiltration in the lungs. Knockdown of Fbxo3 suppressed lung pathology in infected mice and improved survival rates. Compared with blood cells from healthy individuals, white blood cells from patients with sepsis showed increased levels of FBXO3 and TRAF proteins and lower levels of FBXL2; this indicates that these F-box proteins might also regulate inflammation in humans. Finally, the authors developed a small-molecule inhibitor, BC-1215, to target the FBXO3–FBXL2 interaction. They found that treatment of human peripheral blood mononuclear cells with BC-1215 inhibited LPSinduced cytokine production, and BC-1215 also showed beneficial antiinflammatory effects in mouse models of sepsis and P. aeruginosa infection. In summary, this study shows that FBXL2 suppresses pro-inflammatory cytokine production by targeting TRAF proteins for ubiquitylation and degradation. By contrast, FBXO3 enhances cytokine responses by inducing the ubiquitylation and degradation of FBXL2. It will be exciting to explore whether small-molecule inhibitors of FBXO3 can have beneficial effects in human inflammatory diseases. Yvonne Bordon S I G N A L L I N G