Inhibition of TRAF6 ubiquitin-ligase activity by PRDX1 leads to inhibition of NFKB activation and autophagy activation

These results suggest that peroxiredoxin 1 negatively regulates TLR4 signaling for nuclear factor kappa-light-chain-enhancer of activated B cells activation and autophagy functions such as bactericidal activity, cancer cell migration, and cancer cell invasion by inhibiting TRAF6 ubiquitin-ligase activity

Yoon Min; Mi-Jeong Kim; Sena Lee; Eunyoung Chun; Ki-Young Lee

2018

Scholarcy highlights

  • TRAF6, a member of the TNF receptor associated factor protein family, is essential for the regulation of toll like receptormediated signaling
  • Levels of pro-inflammatory cytokines such as interleukin 6 and interleukin 1 beta produced in response to LPS stimulation were markedly decreased in MYC-peroxiredoxin 1-overexpressed cells), suggesting that PRDX1 negatively regulated the activation of nuclear factor kappa-light-chain-enhancer of activated B cells induced by TLR4 stimulation
  • Our biochemical study revealed that PRDX1 interacted with the ring finger domain of TRAF6, which critically affected TRAF6 ubiquitin-ligase activity, resulting in attenuation of ubiquitination of TRAF6, evolutionarily conserved signaling intermediate in Toll pathways, and beclin 1
  • Inhibition of TRAF6 and ECSIT ubiquitination led to inhibition of TLR4-induced activation of NFKB while inhibition of BECN1 ubiquitination led to inhibition of TLR4-induced autophagy activation
  • We found that PRDX1 interacted with the ring finger domain of TRAF6, resulting in the attenuation of ubiquitination of TRAF6 and ECSIT proteins and inhibition of NFKB activation induced by TLR4 stimulation
  • These results suggest that TRAF6 functions as an E3 ligase to ubiquitinate BECN1 whereas PRDX1 inhibits the ubiquitination of BECN1 through inhibiting TRAF6 ubiquitin-ligase activity to control the extent of autophagy elicited by TLR4 signaling
  • Our data showed that TLR4-induced autophagy activation was significantly enhanced in PRDX1KD THP-1 cells

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