A Noncanonical Mechanism of Nrf2 Activation by Autophagy Deficiency: Direct Interaction between Keap1 and p62

By Alexandria Lau, Xiao-jun Wang, Fei Zhao, N. Villeneuve, Tongde Wu, T. Jiang, Zheng Sun, E. White, Donna D. Zhang. Molecular and Cellular Biology, 2010

824 citations recorded by the source corpus.

Subfields: Epidemiology, Materials Chemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9db4f91ba3e71fa07f5c6c1ce419ef02f4ba45b4

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Citations in the corpus

Oxidative stress and autophagy: the clash between damage and metabolic needs (2014, background): “ECH- associated protein 1 (Keap1) that functions as an adapter protein of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2.(82,83) In agreement with this”
p62 links autophagy and Nrf2 signaling. (2015, background): “an autophagy adaptor, and Keap1 [18–22].”
Oxidative stress response and Nrf2 signaling in aging. (2015, positive): “It is increased in response to various stimuli and interacts with Keap1, and causes Keap1 accumulation and subsequent autophagic degradation, resulting in the inhibition of the binding of Keap1 and Nrf2, and inhibition of Keap1-mediated Nrf2 degradation [319].”
The dynamic nature of autophagy in cancer. (2011, background): “Another link of elevated p62 to tumorigenesis was provided by two groups (Komatsu et al. 2010; Lau et al. 2010) who demonstrated that p62 binds to Keap1, leading to the up-regulation of NRF2, a transcription factor whose functions include the coordination of an antioxidant defense.”
Transcriptional Regulation by Nrf2 (2017, background): “When autophagy is impaired, p62 levels are elevated, leading to degradation of Keap1 and consequent Nrf2 stabilization (26, 83, 90).”
The emerging role of the Nrf2–Keap1 signaling pathway in cancer (2013, background): “…is degraded through the autophagy–lysosome pathway (Taguchi et al. 2012), siRNA-mediated knockdown of p62 increased the half-life of Keap1 twofold, increased the levels of Keap1, lowered the level of Nrf2, and reduced the expression of Nrf2 target genes (Copple et al. 2010; Lau et al. 2010, 2013).”
Nrf2, the Master Regulator of Anti-Oxidative Responses (2017, background): “p62/SQSTM1 comp tes with Nrf2 for binding to Keap1, thereby leading to decreased degradation of Nrf2 and increased activity [28,107,108].”
Autophagy-deficient mice develop multiple liver tumors. (2011, background): “It has been shown that p62 accumulation traps and inactivates Keap1, a key regulator of the oxidative stress response, leading to activation of the transcription factor Nrf2 (Komatsu et al. 2010; Lau et al. 2010).”
An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation (2020, background): “Under normal physiological conditions, p62 is constantly degraded during autophagy; however, under pathological oxidative stress conditions p62 accumulates and competitively binds to Keap1, thus causing the release of Nrf2 and the activation of its downstream target genes [116].”
Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. (2014, background): “…MURF2, and KEAP1, are among the direct interaction partners of p62 (Fusco et al., 2012; Jain et al., 2010; Komatsu et al., 2010; Lange et al., 2005; Lau et al., 2010; Moscat and Diaz-Meco, 2009), which may promote ubiquitination of p62 substrates, impacting inclusion body formation and aggrephagy.”
Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells (2011, background): “…overproduction of p62 or autophagy deficiency competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 followed by transcriptional activation of Nrf2 target genes (Copple et al., 2010; Jain et al., 2010; Komatsu et al., 2010; Lau et al., 2010; Riley et al., 2010).”