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

Mol Cell. 2013 Sep 12;51(5):618-31. doi: 10.1016/j.molcel.2013.08.003. Epub 2013 Sep 5.

Abstract

The Keap1-Nrf2 system and autophagy are both involved in the oxidative-stress response, metabolic pathways, and innate immunity, and dysregulation of these processes is associated with pathogenic processes. However, the interplay between these two pathways remains largely unknown. Here, we show that phosphorylation of the autophagy-adaptor protein p62 markedly increases p62's binding affinity for Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2. Thus, p62 phosphorylation induces expression of cytoprotective Nrf2 targets. p62 is assembled on selective autophagic cargos such as ubiquitinated organelles and subsequently phosphorylated in an mTORC1-dependent manner, implying coupling of the Keap1-Nrf2 system to autophagy. Furthermore, persistent activation of Nrf2 through accumulation of phosphorylated p62 contributes to the growth of human hepatocellular carcinomas (HCCs). These results demonstrate that selective autophagy and the Keap1-Nrf2 pathway are interdependent, and that inhibitors of the interaction between phosphorylated p62 and Keap1 have potential as therapeutic agents against human HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adenoma / metabolism
  • Adenoma / pathology
  • Amino Acid Sequence
  • Animals
  • Autophagy / physiology*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / chemistry*
  • Cytoskeletal Proteins / metabolism*
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Molecular Sequence Data
  • Multiprotein Complexes / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • Phosphorylation
  • Sequestosome-1 Protein
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Heat-Shock Proteins
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Multiprotein Complexes
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1

Associated data

  • PDB/3WDZ