期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 25, 页码 15687-15696出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.643700
关键词
inflammation; NF-B; peptide array; peptides; transcription; BCL-3
资金
- Science Foundation Ireland [08/IN.1/B1843]
- Biotechnology and Biological Sciences Research Council [BB/M003671/1]
- Institute of Infection, Immunity and Inflammation at the University of Glasgow
- Engineering and Physical Sciences Research Council [EP/L014165/1]
- Biotechnology and Biological Sciences Research Council [BB/M003671/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/L014165/1] Funding Source: researchfish
- Medical Research Council [MR/M010694/1] Funding Source: researchfish
- Science Foundation Ireland (SFI) [08/IN.1/B1843] Funding Source: Science Foundation Ireland (SFI)
- BBSRC [BB/M003671/1] Funding Source: UKRI
- EPSRC [EP/L014165/1] Funding Source: UKRI
- MRC [MR/M010694/1] Funding Source: UKRI
The NF-B transcriptional response is tightly regulated by a number of processes including the phosphorylation, ubiquitination, and subsequent proteasomal degradation of NF-B subunits. The IB family protein BCL-3 stabilizes a NF-B p50 homodimer.DNA complex through inhibition of p50 ubiquitination. This complex inhibits the binding of the transcriptionally active NF-B subunits p65 and c-Rel on the promoters of NF-B target genes and functions to suppress inflammatory gene expression. We have previously shown that the direct interaction between p50 and BCL-3 is required for BCL-3-mediated inhibition of pro-inflammatory gene expression. In this study we have used immobilized peptide array technology to define regions of BCl-3 that mediate interaction with p50 homodimers. Our data show that BCL-3 makes extensive contacts with p50 homodimers and in particular with ankyrin repeats (ANK) 1, 6, and 7, and the N-terminal region of Bcl-3. Using these data we have designed a BCL-3 mimetic peptide based on a region of the ANK1 of BCL-3 that interacts with p50 and shares low sequence similarity with other IB proteins. When fused to a cargo carrying peptide sequence this BCL-3-derived peptide, but not a mutated peptide, inhibited Toll-like receptor-induced cytokine expression in vitro. The BCL-3 mimetic peptide was also effective in preventing inflammation in vivo in the carrageenan-induced paw edema mouse model. This study demonstrates that therapeutic strategies aimed at mimicking the functional activity of BCL-3 may be effective in the treatment of inflammatory disease.
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