TRAF2 Suppresses Basal IKK Activity in Resting Cells and TNFα Can Activate IKK in TRAF2 and TRAF5 Double Knockout Cells

Laiqun Zhang; Ken Blackwell; Gregory S Thomas; Shujie Sun; Wen-Chen Yeh; Hasem Habelhah

doi:10.1016/j.jmb.2009.04.054

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TRAF2 Suppresses Basal IKK Activity in Resting Cells and TNFα Can Activate IKK in TRAF2 and TRAF5 Double Knockout Cells

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TRAF2 Suppresses Basal IKK Activity in Resting Cells and TNFα Can Activate IKK in TRAF2 and TRAF5 Double Knockout Cells

Laiqun Zhang, Ken Blackwell, Gregory S Thomas, Shujie Sun, Wen-Chen Yeh and Hasem Habelhah

Journal of molecular biology, Vol.389(3), pp.495-510

06/12/2009

DOI: 10.1016/j.jmb.2009.04.054

PMCID: PMC2730456

PMID: 19409903

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https://www.ncbi.nlm.nih.gov/pmc/articles/2730456View

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Abstract

Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) and TRAF5 are adapter proteins involved in TNFα-induced activation of the c-Jun N-terminal kinase and nuclear factor κB (NF-κB) pathways. Currently, TNFα-induced NF-κB activation is believed to be impaired in TRAF2 and TRAF5 double knockout (T2/5 DKO) cells. Here, we report instead that T2/5 DKO cells exhibit high basal IκB kinase (IKK) activity and elevated expression of NF-κB-dependent genes in unstimulated conditions. Although TNFα-induced receptor-interacting protein 1 ubiquitination is indeed impaired in T2/5 DKO cells, TNFα stimulation further increases IKK activity in these cells, resulting in significantly elevated expression of NF-κB target genes to a level higher than that in wild-type cells. Inhibition of NIK in T2/5 DKO cells attenuates basal IKK activity and restores robust TNFα-induced IKK activation to a level comparable with that seen in wild-type cells. This suggests that TNFα can activate IKK in the absence of TRAF2 and TRAF5 expression and receptor-interacting protein 1 ubiquitination. In addition, both the basal and TNFα-induced expression of anti-apoptotic proteins are normal in T2/5 DKO cells, yet these DKO cells remain sensitive to TNFα-induced cell death, due to the impaired recruitment of anti-apoptotic proteins to the TNFR1 complex in the absence of TRAF2. Thus, our data demonstrate that TRAF2 negatively regulates basal IKK activity in resting cells and inhibits TNFα-induced cell death by recruiting anti-apoptotic proteins to the TNFR1 complex rather than by activating the NF-κB pathway.

NF-κB

apoptosis

TNFα

TRAF2

TRAF5

Details

Title: Subtitle: TRAF2 Suppresses Basal IKK Activity in Resting Cells and TNFα Can Activate IKK in TRAF2 and TRAF5 Double Knockout Cells
Creators: Laiqun Zhang - Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, 1173ML, Iowa City, IA 52242-1087, USA
Ken Blackwell - Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, 1173ML, Iowa City, IA 52242-1087, USA
Gregory S Thomas - Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, 1173ML, Iowa City, IA 52242-1087, USA
Shujie Sun - Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, 1173ML, Iowa City, IA 52242-1087, USA
Wen-Chen Yeh - The Campbell Family Institute for Breast Cancer Research, University of Toronto, Toronto, Ontario, M5G 2C1 Canada
Hasem Habelhah - Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, 1173ML, Iowa City, IA 52242-1087, USA
Resource Type: Journal article
Publication Details: Journal of molecular biology, Vol.389(3), pp.495-510
DOI: 10.1016/j.jmb.2009.04.054
PMID: 19409903
PMCID: PMC2730456
NLM abbreviation: J Mol Biol
ISSN: 0022-2836
eISSN: 1089-8638
Publisher: Elsevier Ltd
Language: English
Date published: 06/12/2009
Academic Unit: Pathology; Medicine Administration
Record Identifier: 9984047867102771

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