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Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy

Yoshinobu Ichimura1, Satoshi Waguri, Yu-Shin Sou

  • 1Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.

Molecular Cell
|September 10, 2013
PubMed

Insights

Phosphorylation of p62 enhances its Keap1 binding, activating the Nrf2 pathway. This p62-Keap1 interaction drives hepatocellular carcinoma growth, offering therapeutic targets.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Oncology

Background:

  • The Keap1-Nrf2 system and autophagy are crucial for oxidative stress response, metabolism, and immunity.
  • Dysregulation of these pathways is linked to various diseases.
  • The interaction between Keap1-Nrf2 and autophagy remains poorly understood.

Purpose of the Study:

  • To investigate the interplay between the Keap1-Nrf2 pathway and autophagy.
  • To elucidate the role of p62 phosphorylation in this interaction.
  • To explore the implications for hepatocellular carcinoma (HCC) pathogenesis.

Main Methods:

  • Investigated the effect of p62 phosphorylation on Keap1 binding affinity.
  • Examined the assembly and phosphorylation of p62 in selective autophagy.
  • Assessed the role of the p62-Keap1 interaction in HCC growth.

Main Results:

  • p62 phosphorylation significantly increases its binding affinity to Keap1.
  • This interaction leads to the induction of cytoprotective Nrf2 target genes.
  • Accumulation of phosphorylated p62 promotes human HCC growth.
  • Selective autophagy and the Keap1-Nrf2 pathway were found to be interdependent.

Conclusions:

  • p62 phosphorylation couples selective autophagy to the Keap1-Nrf2 pathway.
  • The interaction between phosphorylated p62 and Keap1 is critical for HCC progression.
  • Inhibitors targeting the p62-Keap1 interaction show potential for HCC therapy.

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