p62/SQSTM1 Is a Target Gene for Transcription Factor NRF2 and Creates a Positive Feedback Loop by Inducing Antioxidant Response Element-driven Gene Transcription*

By Ashish Jain, T. Lamark, E. Sjøttem, Kenneth Bowitz Larsen, Jane Atesoh Awuh, Aud Øvervatn, Michael T. McMahon, J. Hayes, T. Johansen. Journal of Biological Chemistry, 2010

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The p62/SQSTM1 (sequestosome 1) protein, which acts as a cargo receptor for autophagic degradation of ubiquitinated targets, is up-regulated by various stressors. Induction of the p62 gene by oxidative stress is mediated by NF-E2-related factor 2 (NRF2) and, at the same time, p62 protein contributes to the activation of NRF2, but hitherto the mechanisms involved were not known. Herein, we have mapped an antioxidant response element (ARE) in the p62 promoter that is responsible for its induction by oxidative stress via NRF2. Chromatin immunoprecipitation and gel mobility-shift assays verified that NRF2 binds to this cis-element in vivo and in vitro. Also, p62 docks directly onto the Kelch-repeat domain of Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated the KEAP1 interacting region (KIR), thereby blocking binding between KEAP1 and NRF2 that leads to ubiquitylation and degradation of the transcription factor. The KIR motif in p62 is located immediately C-terminal to the LC3-interacting region (LIR) and resembles the ETGE motif utilized by NRF2 for its interaction with KEAP1. KIR is required for p62 to stabilize NRF2, and inhibition of KEAP1 by p62 occurs from a cytoplasmic location within the cell. The LIR and KIR motifs cannot be engaged simultaneously by LC3 and KEAP1, but because p62 is polymeric the interaction between KEAP1 and p62 leads to accumulation of KEAP1 in p62 bodies, which is followed by autophagic degradation of KEAP1. Our data explain how p62 contributes to activation of NRF2 target genes in response to oxidative stress through creating a positive feedback loop.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4e832ba9e89fef64b360c10b3e119e96a9bbc8d0

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Citations in the corpus

p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation (2016, neutral): “Keap1 to free Nrf2, which can then induce p62 synthesis [62].”
Transcriptional Regulation by Nrf2 (2017, background): “Of note, p62 is an Nrf2 target gene, thus creating another positive feedback loop (62).”
The cytoprotective role of the Keap1–Nrf2 pathway (2011, background): “In addition to Nrf2, Keap1 has also been shown to bind to other proteins, including IKKb, p62, and PGAM5 (Lo and Hannink 2006a; Lo and Hannink 2008; Lee et al. 2009; Komatsu et al. 2010; Lau et al. 2010; Jain et al. 2010; Kim et al. 2010).”
p62 links autophagy and Nrf2 signaling. (2015, background): “This adjacency was shown to cause competitive binding between LC3 and Keap1 to p62 [20].”
Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism (2016, background): “identified p62 as a direct Nrf2-regulated gene as Nrf2 binds to ARE sequence in the p62 promoter, leading to its increased expression [171].”
The mitophagy pathway and its implications in human diseases (2023, background): “55 NDP52 is a multifunctional autophagy adapter composed of an N-terminal SKIP carboxyl homology (SKICH) domain, a central coiled-coil domain, and a C-terminal ubiquitin-binding zinc ﬁ nger (ZF).”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, neutral): “In fact, SQSTM1 may, itself, be transcriptionally induced by NFE2L2.(430) Furthermore, it is preferable to examine endogenous SQSTM1 because overexpression of this protein”
Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation (2023, background): “Although there is growing knowledge of the interaction between Nrf2 and mitochondria, its function in mitophagy has just been investigated lately.”
Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution (2011, background): “…covalent binding of an actin monomer (43 kDa) (Kang et al. 2002) or tetra-ubiquitin conjugation (Li et al. 2005). p62 accumulation in human cancer As mentioned previously, p62 has been identified as an inducer of Nrf2 (Copple et al. 2010; Jain et al. 2010; Komatsu et al. 2010; Lau et al. 2010).”
Autophagy in malignant transformation and cancer progression (2015, positive): “…derepression of BECN1), and the NRF2-dependent transactivation of genes encoding several autophagy receptors, including p62 and calcium binding and coiled-coil domain 2 (CALCOCO2, best known as NDP52) (Wei et al , 2008; Jain et al , 2010; DeNicola et al , 2011; Lock et al , 2011; Jo et al , 2014).”
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).”