| RRC ID |
61346
|
| 著者 |
Colleran A, Ryan A, O'Gorman A, Mureau C, Liptrot C, Dockery P, Fearnhead H, Egan LJ.
|
| タイトル |
Autophagosomal IkappaB alpha degradation plays a role in the long term control of tumor necrosis factor-alpha-induced nuclear factor-kappaB (NF-kappaB) activity.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
Transcription factor NF-κB is persistently activated in many chronic inflammatory diseases and cancers. The short term regulation of NF-κB is well understood, but little is known about the mechanisms of its long term activation. We studied the effect of a single application of TNF-α on NF-κB activity for up to 48 h in intestinal epithelial cells. Results show that NF-κB remained persistently activated up to 48 h after TNF-α and that the long term activation of NF-κB was accompanied by a biphasic degradation of IκBα. The first phase of IκBα degradation was proteasome-dependent, but the second was not. Further investigation showed that TNF-α stimulated formation of autophagosomes in intestinal epithelial cells and that IκBα co-localized with autophagosomal vesicles. Pharmacological or genetic blockade of autophagosome formation or the inhibition of lysosomal proteases decreased TNF-α-induced degradation of IκBα and lowered NF-κB target gene expression. Together, these findings indicate a role of autophagy in the control of long term NF-κB activity. Because abnormalities in autophagy have been linked to ineffective innate immunity, we propose that alterations in NF-κB may mediate this effect.
|
| 巻・号 |
286(26)
|
| ページ |
22886-93
|
| 公開日 |
2011-7-1
|
| DOI |
10.1074/jbc.M110.199950
|
| PII |
S0021-9258(19)48826-1
|
| PMID |
21454695
|
| PMC |
PMC3123056
|
| MeSH |
Animals
Autophagy / physiology*
Humans
I-kappa B Proteins / genetics
I-kappa B Proteins / immunology
I-kappa B Proteins / metabolism*
Immunity, Innate / physiology
Mice
Mice, Knockout
NF-KappaB Inhibitor alpha
NF-kappa B / genetics
NF-kappa B / immunology
NF-kappa B / metabolism*
NIH 3T3 Cells
Phagosomes / genetics
Phagosomes / immunology
Phagosomes / metabolism*
Time Factors
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / immunology
Tumor Necrosis Factor-alpha / metabolism*
|
| IF |
4.238
|
| リソース情報 |
| ヒト・動物細胞 |
Atg5^(+/+)MEF(RCB2710)
Atg5^(-/-)MEF(RCB2711) |
