Brefeldin A-Inhibited Guanine Nucleotide-Exchange Factor 1 (BIG1) Governs the Recruitment of Tumor Necrosis Factor Receptor-Associated Factor 2 (TRAF2) to Tumor Necrosis Factor Receptor 1 (TNFR1) Signaling Complexes

Int J Mol Sci. 2016 Nov 9;17(11):1869. doi: 10.3390/ijms17111869.


Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a critical mediator of tumor necrosis factor-α (TNF-α) signaling. However, the regulatory mechanisms of TRAF2 are not fully understood. Here we show evidence that TRAF2 requires brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) to be recruited into TNF receptor 1 (TNFR1) signaling complexes. In BIG1 knockdown cells, TNF-α-induced c-Jun N-terminal kinase (JNK) activation was attenuated and the sensitivity to TNF-α-induced apoptosis was increased. Since these trends correlated well with those of TRAF2 deficient cells as previously demonstrated, we tested whether BIG1 functions as an upstream regulator of TRAF2 in TNFR1 signaling. As expected, we found that knockdown of BIG1 suppressed TNF-α-dependent ubiquitination of TRAF2 that is required for JNK activation, and impaired the recruitment of TRAF2 to the TNFR1 signaling complex (complex I). Moreover, we found that the recruitment of TRAF2 to the death-inducing signaling complex termed complex II was also impaired in BIG1 knockdown cells. These results suggest that BIG1 is a key component of the machinery that drives TRAF2 to the signaling complexes formed after TNFR1 activation. Thus, our data demonstrate a novel and unexpected function of BIG1 that regulates TNFR1 signaling by targeting TRAF2.

Keywords: BIG1; JNK; TRAF2; apoptosis; tumor necrosis factor-α (TNF-α).

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Gene Expression Regulation
  • Genes, Reporter
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism
  • HeLa Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein Transport
  • Proteolysis / drug effects
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type I / genetics*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction / genetics*
  • TNF Receptor-Associated Factor 2 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 2 / genetics*
  • TNF Receptor-Associated Factor 2 / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitination / drug effects


  • ARFGEF1 protein, human
  • Guanine Nucleotide Exchange Factors
  • NF-kappa B
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor, Type I
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Luciferases
  • JNK Mitogen-Activated Protein Kinases