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RIPK1 is not essential for TNFR1-induced activation of NF-κB


Wong, W Wei-Lynn; Gentle, I G; Nachbur, U; Carter, H; Vaux, D L; Silke, J (2010). RIPK1 is not essential for TNFR1-induced activation of NF-κB. Cell Death and Differentiation, 17:482-487.

Abstract

On TNF binding, receptor-interacting protein kinase 1 (RIPK1) is recruited to the cytoplasmic domain of TNFR1, at which it becomes ubiquitylated and serves as a platform for recruitment and activation of NEMO/IKK1/IKK2 and TAK1/TAB2. RIPK1 is commonly thought to be required for the activation of canonical NF-κB and for inhibition TNFR1-induced apoptosis. RIPK1 has, however, also been reported to be essential for TNFR1-induced apoptosis when cIAPs are depleted. To determine the role of RIPK1 in TNF/IAP antagonist-induced death, we compared wild type (WT) and RIPK1−/− mouse embryonic fibroblasts (MEFs) treated with these compounds. On being treated with TNF plus IAP antagonist, RIPK1−/− MEFs survived, unlike WT MEFs, demonstrating a killing activity of RIPK1. Surprisingly, however, on being treated with TNF alone, RIPK1−/− MEFs activated canonical NF-κB and did not die. Furthermore, several cell types from E18 RIPK1−/− embryos seem to activate NF-κB in response to TNF. These data indicate that models proposing that RIPK1 is essential for TNFR1 to activate canonical NF-κB are incorrect.

Abstract

On TNF binding, receptor-interacting protein kinase 1 (RIPK1) is recruited to the cytoplasmic domain of TNFR1, at which it becomes ubiquitylated and serves as a platform for recruitment and activation of NEMO/IKK1/IKK2 and TAK1/TAB2. RIPK1 is commonly thought to be required for the activation of canonical NF-κB and for inhibition TNFR1-induced apoptosis. RIPK1 has, however, also been reported to be essential for TNFR1-induced apoptosis when cIAPs are depleted. To determine the role of RIPK1 in TNF/IAP antagonist-induced death, we compared wild type (WT) and RIPK1−/− mouse embryonic fibroblasts (MEFs) treated with these compounds. On being treated with TNF plus IAP antagonist, RIPK1−/− MEFs survived, unlike WT MEFs, demonstrating a killing activity of RIPK1. Surprisingly, however, on being treated with TNF alone, RIPK1−/− MEFs activated canonical NF-κB and did not die. Furthermore, several cell types from E18 RIPK1−/− embryos seem to activate NF-κB in response to TNF. These data indicate that models proposing that RIPK1 is essential for TNFR1 to activate canonical NF-κB are incorrect.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:13 Jun 2012 15:27
Last Modified:05 Apr 2016 15:33
Publisher:Nature Publishing Group
ISSN:1350-9047
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/cdd.2009.178
PubMed ID:19927158

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