Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis

Free Radic Biol Med. 2011 May 1;50(9):1186-95. doi: 10.1016/j.freeradbiomed.2011.01.033. Epub 2011 Feb 2.

Abstract

Oxidative stress, perturbations in the cellular thiol level and redox balance, affects many cellular functions, including signaling pathways. This, in turn, may cause the induction of autophagy or apoptosis. The NRF2/KEAP1 signaling pathway is the main pathway responsible for cell defense against oxidative stress and maintaining the cellular redox balance at physiological levels. The relation between NRF2/KEAP1 signaling and regulation of apoptosis and autophagy is not well understood. In this hypothesis article we discuss how KEAP1 protein and its direct interactants (such as PGAM5, prothymosin α, FAC1 (BPTF), and p62) provide a molecular foundation for a possible cross-talk between NRF2/KEAP1, apoptosis, and autophagy pathways. We present a hypothesis for how NRF2/KEAP1 may interfere with the cellular apoptosis-regulatory machinery through activation of the ASK1 kinase by a KEAP1 binding partner-PGAM5. Based on very recent experimental evidence, new hypotheses for a cross-talk between NF-κB and the NRF2/KEAP1 pathway in the context of autophagy-related "molecular hub" protein p62 are also presented. The roles of KEAP1 molecular binding partners in apoptosis regulation during carcinogenesis and in neurodegenerative diseases are also discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Motifs
  • Animals
  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / metabolism
  • Apoptosis*
  • Autophagy*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Oxidation-Reduction
  • Oxidative Stress*
  • Phosphoprotein Phosphatases
  • Phosphorylation
  • Protein Binding
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Reactive Oxygen Species / metabolism
  • Sequestosome-1 Protein
  • Signal Transduction / physiology*
  • Sulfhydryl Compounds / metabolism*
  • Thymosin / analogs & derivatives
  • Thymosin / genetics
  • Thymosin / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Nuclear
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • Mitochondrial Proteins
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nerve Tissue Proteins
  • Protein Precursors
  • Reactive Oxygen Species
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sulfhydryl Compounds
  • Transcription Factors
  • fetal Alzheimer antigen
  • prothymosin alpha
  • Thymosin
  • MAP Kinase Kinase Kinase 5
  • PGAM5 protein, human
  • Phosphoprotein Phosphatases