title: Autophagosomal IkappaB alpha degradation plays a role in the long term control of tumor necrosis factor-alpha-induced nuclear factor-kappaB (NF-kappaB) activity.
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.
authors: Department of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
authors: Amy
authors: A
authors: Colleran
authors: Aideen
authors: A
authors: Ryan
authors: Angela
authors: A
authors: O'Gorman
authors: Coralie
authors: C
authors: Mureau
authors: Catherine
authors: C
authors: Liptrot
authors: Peter
authors: P
authors: Dockery
authors: Howard
authors: H
authors: Fearnhead
authors: Laurence J
authors: LJ
authors: Egan
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010588:Phagosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha