Autophagosomal iκbα degradation plays a role in the long term control of tumor necrosis factor-α-induced nuclear factor-κb (nf-κb) activity
Colleran, Amy ; Ryan, Aideen ; O'Gorman, Angela ; Mureau, Coralie ; Liptrot, Catherine ; Dockery, Peter ; Fearnhead, Howard ; Egan, Laurence J.
Colleran, Amy
Ryan, Aideen
O'Gorman, Angela
Mureau, Coralie
Liptrot, Catherine
Dockery, Peter
Fearnhead, Howard
Egan, Laurence J.
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Publication Date
2011-03-31
Type
Article
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Citation
Colleran, Amy; Ryan, Aideen; O'Gorman, Angela; Mureau, Coralie; Liptrot, Catherine; Dockery, Peter; Fearnhead, Howard; Egan, Laurence J. (2011). Autophagosomal iκbα degradation plays a role in the long term control of tumor necrosis factor-α-induced nuclear factor-κb (nf-κb) activity. Journal of Biological Chemistry 286 (26), 22886-22893
Abstract
Transcription factor NF-kappa B is persistently activated in many chronic inflammatory diseases and cancers. The short term regulation of NF-kappa B 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-alpha on NF-kappa B activity for up to 48 h in intestinal epithelial cells. Results show that NF-kappa B remained persistently activated up to 48 h after TNF-alpha and that the long term activation of NF-kappa B was accompanied by a biphasic degradation of I kappa B alpha. The first phase of I kappa B alpha degradation was proteasome-dependent, but the second was not. Further investigation showed that TNF-alpha stimulated formation of autophagosomes in intestinal epithelial cells and that I kappa B alpha co-localized with autophagosomal vesicles. Pharmacological or genetic blockade of autophagosome formation or the inhibition of lysosomal proteases decreased TNF-alpha-induced degradation of I kappa B alpha and lowered NF-kappa B target gene expression. Together, these findings indicate a role of autophagy in the control of long term NF-kappa B activity. Because abnormalities in autophagy have been linked to ineffective innate immunity, we propose that alterations in NF-kappa B may mediate this effect.
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Publisher
American Society for Biochemistry & Molecular Biology (ASBMB)
Publisher DOI
10.1074/jbc.m110.199950
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Attribution-NonCommercial-NoDerivs 3.0 Ireland