title: ER stress activates NF-κB by integrating functions of basal IKK activity, IRE1 and PERK.
abstract: NF-κB, a transcription factor, becomes activated during the Unfolded Protein Response (UPR), an endoplasmic reticulum (ER) stress response pathway. NF-κB is normally held inactive by its inhibitor, IκBα. Multiple cellular pathways activate IKK (IκBα Kinase) which phosphorylate IκBα leading to its degradation and NF-κB activation. Here, we find that IKK is required for maximum activation of NF-κB in response to ER stress. However, unlike canonical NFκB activation, IKK activity does not increase during ER stress, but rather the level of basal IKK activity is critical for determining the extent of NF-κB activation. Furthermore, a key UPR initiator, IRE1, acts to maintain IKK basal activity through IRE1's kinase, but not RNase, activity. Inputs from IRE1 and IKK, in combination with translation repression by PERK, another UPR initiator, lead to maximal NF-κB activation during the UPR. These interdependencies have a significant impact in cancer cells with elevated IKK/NF-κB activity such as renal cell carcinoma cells (786-0). Inhibition of IKK by an IKK inhibitor, which significantly decreases NF-κB activity, is overridden by UPR induction, arguing for the importance of considering UPR activation in cancer treatment.
authors.affiliation: Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Arvin B
authors.initials: AB
authors.lastname: Tam
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Mercado
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Maho
authors.initials: M
authors.lastname: Niwa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D006224:Cricetinae; D024202:Electrophoretic Mobility Shift Assay; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004722:Endoribonucleases; D051550:I-kappa B Kinase; D008565:Membrane Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C403982:ERN2 protein, human