The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
A Noncanonical Mechanism of Nrf2 Activation by Autophagy Deficiency: Direct Interaction between Keap1 and p62
Open accessAbstract
In response to stress, cells can utilize several cellular processes, such as autophagy, which is a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. Deregulation of autophagy causes upregulation of p62 and the formation of p62-containing aggregates, which are associated with neurodegenerative diseases and cancer. The Nrf2-Keap1 pathway functions as a critical regulator of the cell's defense mechanism against oxidative stress by controlling the expression of many cellular protective proteins. Under basal conditions, Nrf2 is ubiquitinated by the Keap1-Cul3-E3 ubiquitin ligase complex and targeted to the 26S proteasome for degradation. Upon induction, the activity of the E3 ubiquitin ligase is inhibited through the modification of cysteine residues in Keap1, resulting in the stabilization and activation of Nrf2. In this current study, we identified the direct interaction between p62 and Keap1 and the residues required for the interaction have been mapped to 349-DPSTGE-354 in p62 and three arginines in the Kelch domain of Keap1. Accumulation of endogenous p62 or ectopic expression of p62 sequesters Keap1 into aggregates, resulting in the inhibition of Keap1-mediated Nrf2 ubiquitination and its subsequent degradation by the proteasome. In contrast, overexpression of mutated p62, which loses its ability to interact with Keap1, had no effect on Nrf2 stability, demonstrating that p62-mediated Nrf2 upregulation is Keap1 dependent. These findings demonstrate that autophagy deficiency activates the Nrf2 pathway in a noncanonical cysteine-independent mechanism.
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Cites
Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E.-L., Mizushima, N., Ohsumi, Y., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci20039 · Cited by 2,311
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Self-citationMcMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300931200 · Cited by 1,141 · cited 1×
“The Nrf2 signaling pathway is negatively regulated by Keap1, a substrate adaptor protein of a Cullin 3 (Cul3)-Rbx1-E3 ubiquitin ligase complex that is responsible for the ubiquitination and proteasomal degradation of Nrf2 (3, 13, 27, 29).”
BackgroundTong, K. I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., & Yamamoto, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.8.2887-2900.2006 · Cited by 759 · cited 3×
“Binding of both the DLG and ETGE motifs of Nrf2 to the Kelch domain of a Keap1 homodimer is essential in presenting the lysine residues of Nrf2 in the correct orientation to accept ubiquitin (14, 22, 30).”
BackgroundStructural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.013 · Cited by 735 · cited 2×
“Previously, it has been shown that there are three pertinent arginine residues (Arg380, -415, and -483) in the Kelch domain of Keap1 that are responsible for Nrf2 binding (18).”
BackgroundDirect Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
Chen, W., Sun, Z., Wang, X.-J., Jiang, T., Huang, Z., Fang, D., & Zhang, D. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.029 · Cited by 638
Self-citationThe Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm
Zipper, L. M., & Mulcahy, R. T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206530200 · Cited by 366
A genomic screen for activators of the antioxidant response element
Liu, Y., Kern, J. T., Walker, J. R., Johnson, J. A., Schultz, P. G., & Luesch, H. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700898104 · Cited by 196
Cited by
Role of nrf2 in oxidative stress and toxicity
Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903
Oxidative stress and autophagy: The clash between damage and metabolic needs
Filomeni, G., De Zio, D., & Cecconi, F. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.150 · Cited by 2,195
The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968
Nrf2 signaling pathway: pivotal roles in inflammation
Ahmed, S. M. U., Luo, L., Namani, A., Wang, X. J., & Tang, X. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.11.005 · Cited by 1,794
Self-citationNRF2 and the Hallmarks of Cancer
Rojo de la Vega, M., Chapman, E., & Zhang, D. D. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.022 · Cited by 1,672
Self-citation
Metadata
- Authors
- Lau, A., Wang, X.-J., Zhao, F., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E., & Zhang, D. D.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2010-07-01
- Volume
- 30
- Issue
- 13
- Pages
- 3275-3285
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2126934086
- Cited by
- 849
- References
- 9
- FWCI
- 13.59
- Type
- journal article
- Language
- en
- Open access
- green
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- Lau, A., Wang, X.-J., Zhao, F., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E., & Zhang, D. D. (2010). A Noncanonical Mechanism of Nrf2 Activation by Autophagy Deficiency: Direct Interaction between Keap1 and p62. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.00248-10
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