TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice

Laiqun Zhang; Ken Blackwell; Lauren M Workman; Katherine N Gibson-Corley; Alicia K Olivier; Gail A Bishop; Hasem Habelhah

doi:10.1242/jcs.180554

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TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice

Journal article

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Peer reviewed

TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice

Laiqun Zhang, Ken Blackwell, Lauren M Workman, Katherine N Gibson-Corley, Alicia K Olivier, Gail A Bishop and Hasem Habelhah

Journal of cell science, Vol.129(7), pp.1455-1467

04/01/2016

DOI: 10.1242/jcs.180554

PMCID: PMC4852721

PMID: 26872784

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Abstract

The role of TRAF2 and TRAF5 in TNFα-induced NF-κB activation has become complicated owing to the accumulation of conflicting data. Here, we report that 7-day-old TRAF2-knockout (KO) and TRAF2 TRAF5 double KO (TRAF2/5-DKO) mice exhibit enhanced canonical IκB kinase (IKK) and caspase-8 activation in spleen and liver, and that subsequent knockout of TNFα suppresses the basal activity of caspase-8, but not of IKK. In primary TRAF2 KO and TRAF2/5-DKO cells, TNFα-induced immediate IKK activation is impaired, whereas delayed IKK activation occurs normally; as such, owing to elevated basal and TNFα-induced delayed IKK activation, TNFα stimulation leads to significantly increased induction of a subset of NF-κB-dependent genes in these cells. In line with this, both TRAF2 KO and TRAF2/5-DKO mice succumb to a sublethal dose of TNFα owing to increased expression of NF-κB target genes, diarrhea and bradypnea. Notably, depletion of IAP1 and IAP2 (also known as BIRC2 and BIRC3, respectively) also results in elevated basal IKK activation that is independent of autocrine TNFα production and that impairs TNFα-induced immediate IKK activation. These data reveal that TRAF2, IAP1 and IAP2, but not TRAF5, cooperatively regulate basal and TNFα-induced immediate IKK activation.

Tumor Necrosis Factor-alpha - metabolism

Mice, Inbred C57BL

TNF Receptor-Associated Factor 2 - genetics

Tumor Necrosis Factor-alpha - genetics

Caspase 8 - metabolism

Cells, Cultured

TNF Receptor-Associated Factor 2 - metabolism

Apoptosis - genetics

NF-kappa B - metabolism

Baculoviral IAP Repeat-Containing 3 Protein

I-kappa B Kinase - genetics

TNF Receptor-Associated Factor 5 - metabolism

Mice, Knockout

Inhibitor of Apoptosis Proteins - deficiency

TNF Receptor-Associated Factor 5 - genetics

Animals

I-kappa B Kinase - metabolism

Ubiquitin-Protein Ligases - deficiency

Chemokine CCL5 - metabolism

Mice

Mice, Inbred BALB C

Enzyme Activation - genetics

Nitric Oxide Synthase Type II - metabolism

Details

Title: Subtitle: TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice
Creators: Laiqun Zhang - Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA
Ken Blackwell - Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA
Lauren M Workman - Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA
Katherine N Gibson-Corley - Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA
Alicia K Olivier - Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA
Gail A Bishop - Department of Microbiology & Internal Medicine, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA
Hasem Habelhah - Department of Pathology, Carver College of Medicine, University of Iowa, and the Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA hasem-habelhah@uiowa.edu
Resource Type: Journal article
Publication Details: Journal of cell science, Vol.129(7), pp.1455-1467
DOI: 10.1242/jcs.180554
PMID: 26872784
PMCID: PMC4852721
NLM abbreviation: J Cell Sci
ISSN: 0021-9533
eISSN: 1477-9137
Publisher: England
Grant note: P30 ES005605 / NIEHS NIH HHS CA138475 / NCI NIH HHS CA099997 / NCI NIH HHS R01 CA099997 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA138475 / NCI NIH HHS
Language: English
Date published: 04/01/2016
Academic Unit: Microbiology and Immunology; President; Pathology; Ophthalmology and Visual Sciences
Record Identifier: 9984001143902771

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