BAT3 negatively regulates lipopolysaccharide-induced NF-κB signaling through TRAF6

Biochem Biophys Res Commun. 2016 Sep 16;478(2):784-90. doi: 10.1016/j.bbrc.2016.08.025. Epub 2016 Aug 5.

Abstract

TNF receptor-associated factor 6 (TRAF6) plays a critical role in NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, both of which mediate macrophage activation in response to pathogen-associated molecular patterns such as bacterial endotoxin, lipopolysaccharides (LPS). In this study, we investigated whether HLA-B associated transcript-3 (BAT3) regulates LPS-induced macrophage activation. BAT3 physically interacted with TRAF6 in macrophages, and this interaction was enhanced in the cells after LPS treatment. Furthermore, BAT3 inhibited the homo-oligomerization of TRAF6 as well as the interaction between TRAF6 and its downstream kinase transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing TRAF6-mediated signaling events. Intriguingly, TRAF6 mediated ubiquitination of BAT3 and this ubiquitination was crucial for its inhibitory effect on TRAF6-mediated signaling. Depletion of BAT3 by RNA interference resulted in enhancement of LPS-induced activation of the NF-κB signaling with increasing expression levels of pro-inflammatory cytokines. These findings suggest that BAT3 functions as the negative regulator of LPS-induced macrophage activation.

Keywords: BAT3; Lipopolysaccharides; NF-κB; TRAF6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / genetics
  • Cytokines / immunology
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Lipopolysaccharides / pharmacology*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / immunology
  • Macrophage Activation / drug effects*
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Mice
  • Molecular Chaperones / antagonists & inhibitors
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / immunology
  • NF-kappa B / genetics*
  • NF-kappa B / immunology
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / immunology
  • Protein Binding
  • Protein Multimerization
  • Protein Stability
  • Proteolysis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / genetics*
  • TNF Receptor-Associated Factor 6 / immunology
  • Ubiquitination

Substances

  • Bag6 protein, mouse
  • Cytokines
  • Lipopolysaccharides
  • Molecular Chaperones
  • NF-kappa B
  • Nuclear Proteins
  • RNA, Small Interfering
  • TNF Receptor-Associated Factor 6
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7