Negative regulation of Toll-like receptor signaling by NF-B p50 ubiquitination blockade (Science, 2007, 317:675-678)

報告日期: 2007/11/06
報告時間: 16:00/16:50
報告學生: 彭佳琇
講評老師: 凌 斌
附件下載:

Negative regulation of Toll-like receptor signaling by NF-kB p50 ubiquitination blockade

Science, 317: 675-678 (2007)

 

Speaker: Jia-Siou Peng    

Commentator: Dr. Pin Ling      

Place: Room 602

Date: 2007/11/06 16:00-16:50

 

Abstract:

Toll-like receptor (TLR) activation is essential for the development of innate immunity to pathogens. However, prolonged activation of TLRs can render them hyporesponsive to subsequent ligand stimulation, this phenomenon is referred to as TLR tolerance. NF-kB is a master regulator of inflammatory gene expressions and the core component of the TLR-mediated signaling pathways. Bcl-3 interacts with NF-kB p50 and p52 homodimers but its role in the regulation of NF-kB function to date has been unclear. To explore the roles of Bcl-3 in immunity and tolerance, the authors established in vitro model to find that Bcl3/ cells produced more cytokines than wild-type cells upon stimulation with several TLR ligands, and did not affect cell surface marker expression or phagocytotic function. They also found that Bcl-3 and p50 homodimers regulated NF-kB DNA binding and gene transcription. Bcl-3 increases p50 DNA binding by extending the half-life of p50. In addition, Bcl-3 could block p50 homodimer binding to DNA triggers its polyubiquitination and degradation. Subsequently, the author examined whether Bcl-3 played a role in TLR tolerance. They found that this state of Bcl-3-p50 homodimer-mediated promoter hyporesponsiveness is the molecular basis of TLR tolerance. In conclusion, Bcl-3 is a critical regulator of NF-κB-mediated gene expression following TLR stimulation. Bcl-3 enhances the formation of DNA bound complexes by inhibiting p50 ubiquitination and degradation. These findings provide important insights into the molecular mechanisms of TLR signaling and suggest that deleterious inflammatory responses can be effectively controlled by targeting the NF-kB p50 ubiquitination pathway.

 

 

Referance:

1.      Basak S. et al., A fourth IkappaB protein within the NF-kappaB signaling module. Cell. 128: 369-381 (2007).

2.      Ahmed M. et al., Nuclear factor-kB and the hepatic inflammation fibrosis-cancer axis. Hepatology. 46: 590-597 (2007).