NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling

NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling

TNF receptor 1 (TNFR1) ligation can result in cell survival or cell death. What determines which of the two opposing responses is triggered is not fully understood. The current model suggests that it is the activation of the NF-κB pathway and its induction of pro-survival genes, or the lack thereof,...

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Main Authors: Legarda-Addison, Diana, Hase, Hidenori, O'Donnell, Marie Anne, Ting, Adrian T.
Format: Online
Language:English
Published: 2009
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728158/
id pubmed-2728158
recordtype oai_dc
spelling pubmed-27281582010-03-01 NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling Legarda-Addison, Diana Hase, Hidenori O'Donnell, Marie Anne Ting, Adrian T. Article TNF receptor 1 (TNFR1) ligation can result in cell survival or cell death. What determines which of the two opposing responses is triggered is not fully understood. The current model suggests that it is the activation of the NF-κB pathway and its induction of pro-survival genes, or the lack thereof, which determines the outcome. NF-κB essential modifier (NEMO)/IκB kinase gamma (IKKγ)-deficient cells are highly sensitive to apoptosis and since NEMO is essential for NF-κB activation, it has been assumed that this is due to the lack of NF-κB. This study demonstrates that this assumption was incorrect and that NEMO has another anti-apoptotic function that is independent of its role in the NF-κB pathway. NEMO prevents receptor interacting protein-1 (RIP1) from engaging CASPASE-8 prior to NF-κB-mediated induction of anti-apoptotic genes. Without NEMO, RIP1 associates with CASPASE-8 resulting in rapid tumor necrosis factor (TNF)-induced apoptosis. These results suggest that there are two cell death checkpoints following TNF stimulation: an early transcription-independent checkpoint whereby NEMO restrains RIP1 from activating the caspase cascade, followed by a later checkpoint dependent on NF-κB-mediated transcription of pro-survival genes. 2009-04-17 2009-09 /pmc/articles/PMC2728158/ /pubmed/19373245 http://dx.doi.org/10.1038/cdd.2009.41 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Legarda-Addison, Diana
Hase, Hidenori
O'Donnell, Marie Anne
Ting, Adrian T.
spellingShingle Legarda-Addison, Diana
Hase, Hidenori
O'Donnell, Marie Anne
Ting, Adrian T.
NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling
author_facet Legarda-Addison, Diana
Hase, Hidenori
O'Donnell, Marie Anne
Ting, Adrian T.
author_sort Legarda-Addison, Diana
title NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling
title_short NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling
title_full NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling
title_fullStr NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling
title_full_unstemmed NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling
title_sort nemo/ikkγ regulates an early nf-κb-independent cell death checkpoint during tnf signaling
description TNF receptor 1 (TNFR1) ligation can result in cell survival or cell death. What determines which of the two opposing responses is triggered is not fully understood. The current model suggests that it is the activation of the NF-κB pathway and its induction of pro-survival genes, or the lack thereof, which determines the outcome. NF-κB essential modifier (NEMO)/IκB kinase gamma (IKKγ)-deficient cells are highly sensitive to apoptosis and since NEMO is essential for NF-κB activation, it has been assumed that this is due to the lack of NF-κB. This study demonstrates that this assumption was incorrect and that NEMO has another anti-apoptotic function that is independent of its role in the NF-κB pathway. NEMO prevents receptor interacting protein-1 (RIP1) from engaging CASPASE-8 prior to NF-κB-mediated induction of anti-apoptotic genes. Without NEMO, RIP1 associates with CASPASE-8 resulting in rapid tumor necrosis factor (TNF)-induced apoptosis. These results suggest that there are two cell death checkpoints following TNF stimulation: an early transcription-independent checkpoint whereby NEMO restrains RIP1 from activating the caspase cascade, followed by a later checkpoint dependent on NF-κB-mediated transcription of pro-survival genes.
publishDate 2009
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728158/
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