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TRAF2 suppresses basal IKK activity in resting cells and TNFalpha can activate IKK in TRAF2 and TRAF5 double knockout

Laiqun Zhang1, Ken Blackwell, Gregory S Thomas

  • 1Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, 1173ML, Iowa City, IA 52242-1087, USA.

Journal of Molecular Biology
|May 5, 2009
PubMed

Insights

Tumor necrosis factor receptor-associated factor 2 (TRAF2) negatively regulates basal IKK activity. TRAF2 also prevents TNFalpha-induced cell death by recruiting anti-apoptotic proteins, independent of NF-kappaB activation.

Area of Science:

  • Immunology
  • Cell Signaling
  • Molecular Biology

Background:

  • Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) and TRAF5 are adapter proteins crucial for TNFalpha signaling.
  • TNFalpha-induced activation of c-Jun N-terminal kinase and nuclear factor kappaB (NF-kappaB) pathways are key cellular responses.
  • Previous studies suggested impaired NF-kappaB activation in TRAF2 and TRAF5 double knockout (T2/5 DKO) cells.

Purpose of the Study:

  • To investigate the role of TRAF2 and TRAF5 in TNFalpha-induced NF-kappaB activation and cell death.
  • To elucidate the mechanisms underlying IkappaB kinase (IKK) activity regulation in the absence of TRAF2 and TRAF5.
  • To determine the specific functions of TRAF2 in mediating anti-apoptotic protein recruitment and cell survival.

Main Methods:

  • Generation and analysis of TRAF2 and TRAF5 double knockout (T2/5 DKO) cells.
  • Assessment of IKK activity, NF-kappaB-dependent gene expression, and receptor-interacting protein 1 ubiquitination.
  • Investigation of anti-apoptotic protein recruitment to the TNFR1 complex.
  • Inhibition of NIK to assess its role in IKK activation.

Main Results:

  • T2/5 DKO cells exhibit high basal IKK activity and elevated NF-kappaB-dependent gene expression.
  • TNFalpha stimulation further enhances IKK activity and gene expression in T2/5 DKO cells, surpassing wild-type levels.
  • TRAF2 is essential for recruiting anti-apoptotic proteins to the TNFR1 complex, thereby inhibiting TNFalpha-induced cell death.
  • TNFalpha can activate IKK independently of TRAF2, TRAF5, and receptor-interacting protein 1 ubiquitination.

Conclusions:

  • TRAF2 negatively regulates basal IKK activity in unstimulated cells.
  • TRAF2 plays a critical role in preventing TNFalpha-induced cell death by facilitating anti-apoptotic protein recruitment to TNFR1.
  • NF-kappaB pathway activation is not the primary mechanism by which TRAF2 and TRAF5 confer resistance to TNFalpha-induced apoptosis.

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