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The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds
Open accessAbstract
Animals have evolved defense systems for surviving in a chemically diverse environment. Such systems should demonstrate plasticity, such as adaptive immunity, enabling a response to even unknown chemicals. The antioxidant transcription factor Nrf2 is activated in response to various electrophiles and induces cytoprotective enzymes that detoxify them. We report here the discovery of a multiple sensing mechanism for Nrf2 activation using zebrafish and 11 Nrf2-activating compounds. First, we showed that six of the compounds tested specifically target Cys-151 in Keap1, the ubiquitin ligase for Nrf2, while two compounds target Cys-273. Second, in addition to Nrf2 and Keap1, a third factor was deemed necessary for responding to three of the compounds. Finally, we isolated a zebrafish mutant defective in its response to seven compounds but not in response to the remaining four. These results led us to categorize Nrf2 activators into six classes and hypothesize that multiple sensing allows enhanced plasticity in the system.
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Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
Self-citationCell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224
Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., & Talalay, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172398899 · Cited by 1,947
Self-citationZhang, D. D., & Hannink, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.22.8137-8151.2003 · Cited by 1,480 · cited 3×
“This result is consistent with previous reports demonstrating that a Cys-273 mutation reduces the Nrf2-repression activity of mouse Keap1 in cultured cells (25, 43, 46) and in transgenic rescued mice (45).”
BackgroundResultWakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M.-I., Kobayashi, A., Yamamoto, M., Kensler, T. W., & Talalay, P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307301101 · Cited by 986 · cited 2×
“This result is consistent with previous reports demonstrating that a Cys-273 mutation reduces the Nrf2-repression activity of mouse Keap1 in cultured cells (25, 43, 46) and in transgenic rescued mice (45).”
ResultTwo-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism
Tong, K. I., Kobayashi, A., Katsuoka, F., & Yamamoto, M. (2006) · Biological Chemistry · doi:10.1515/bc.2006.164 · Cited by 473 · cited 1×
“This hypothesis is based on the “hinge and latch” model that depicts strict regulation of Nrf2 ubiquitination (41).”
BackgroundSelf-citationItoh, K., Mochizuki, M., Ishii, Y., Ishii, T., Shibata, T., Kawamoto, Y., Kelly, V., Sekizawa, K., Uchida, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.1.36-45.2004 · Cited by 407 · cited 2×
“The carrageenan-induced pleurisy model of acute lung injury was used to demonstrate the relationship between Nrf2 activation and anti-inflammation and that accumulation of 15d-PGJ2 mediates this relation ( 11 ).”
BackgroundSelf-citation
Cited by
Reactive oxygen species (ROS) as pleiotropic physiological signalling agents
Sies, H., & Jones, D. P. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0230-3 · Cited by 5,335
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
Environmentally induced oxidative stress in aquatic animals
Lushchak, V. I. (2011) · Aquatic Toxicology · doi:10.1016/j.aquatox.2010.10.006 · Cited by 2,729
Combination therapy in combating cancer
Mokhtari, R. B., Homayouni, T. S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B., & Yeger, H. (2017) · Oncotarget · doi:10.18632/oncotarget.16723 · Cited by 2,543
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
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Metadata
- Authors
- Kobayashi, M., Li, L., Iwamoto, N., Nakajima-Takagi, Y., Kaneko, H., Nakayama, Y., Eguchi, M., Wada, Y., Kumagai, Y., & Yamamoto, M.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-01-01
- Volume
- 29
- Issue
- 2
- Pages
- 493-502
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2069159655
- Cited by
- 638
- References
- 8
- FWCI
- 11.54
- Type
- journal article
- Language
- en
- Open access
- green
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- Kobayashi, M., Li, L., Iwamoto, N., Nakajima-Takagi, Y., Kaneko, H., Nakayama, Y., Eguchi, M., Wada, Y., Kumagai, Y., & Yamamoto, M. (2009). The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.01080-08
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