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Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Shasha Yin1, Wangsen Cao2

  • 1Nanjing University School of Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China.

Molecular and Cellular Biology
|May 28, 2015
PubMed

Insights

Toll-like receptor (TLR) agonists activate the Nrf2 defense pathway by reducing Keap1 levels via autophagy. This process, mediated by p62, is crucial for cellular defense against inflammation and infection.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Signaling

Background:

  • Toll-like receptors (TLRs) are critical immune sensors that initiate inflammatory and tissue repair responses.
  • The Nrf2 pathway is a master regulator of cellular defense against oxidative stress and inflammation, vital for combating infection and disease.
  • The precise mechanism linking TLR activation to Nrf2 pathway induction remains incompletely understood.

Purpose of the Study:

  • To elucidate the molecular events mediating Toll-like receptor (TLR)-induced activation of the Nrf2 signaling pathway.
  • To identify the key proteins and cellular processes involved in the crosstalk between TLRs and Nrf2.

Main Methods:

  • Utilized Toll-like receptor (TLR) agonists, including lipopolysaccharide (LPS).
  • Investigated protein expression and localization using techniques such as Western blotting and immunofluorescence.
  • Analyzed protein-protein interactions and degradation pathways, focusing on Keap1, Nrf2, p62, and LC3-II.
  • Employed genetic manipulation (gene knockout and mutant protein expression) to assess the necessity of specific proteins like p62.

Main Results:

  • TLR agonists activate Nrf2 signaling by inducing the degradation of Keap1, a key inhibitor of Nrf2.
  • Keap1 degradation is mediated by autophagy, involving the increased expression and association of p62 and LC3-II with Keap1.
  • p62 is essential for TLR-mediated Keap1 reduction, as demonstrated by the lack of Keap1 degradation in p62-deficient cells or cells expressing a non-interacting Keap1 mutant.
  • Activated Nrf2 translocates to the nucleus, enhancing the transcription of its protective target genes.

Conclusions:

  • TLR signaling activates the Nrf2 pathway through p62-dependent Keap1 degradation via autophagy.
  • This mechanism represents a critical link between innate immune sensing by TLRs and the cellular antioxidant/anti-inflammatory defense system regulated by Nrf2.
  • Understanding this pathway offers potential therapeutic targets for inflammation-associated diseases.

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