The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals
Open accessAbstract
Recognition and repair of cellular damage is crucial if organisms are to survive harmful environmental conditions. In mammals, the Keap1 protein orchestrates this response, but how it perceives adverse circumstances is not fully understood. Herein, we implicate NO, Zn 2+ , and alkenals, endogenously occurring chemicals whose concentrations increase during stress, in this process. By combining molecular modeling with phylogenetic, chemical, and functional analyses, we show that Keap1 directly recognizes NO, Zn 2+ , and alkenals through three distinct sensors. The C288 alkenal sensor is of ancient origin, having evolved in a common ancestor of bilaterans. The Zn 2+ sensor minimally comprises H225, C226, and C613. The most recent sensor, the NO sensor, emerged coincident with an expansion of the NOS gene family in vertebrates. It comprises a cluster of basic amino acids (H129, K131, R135, K150, and H154) that facilitate S -nitrosation of C151. Taken together, our data suggest that Keap1 is a specialized sensor that quantifies stress by monitoring the intracellular concentrations of NO, Zn 2+ , and alkenals, which collectively serve as second messengers that may signify danger and/or damage.
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Cites
Cell 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
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McMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300931200 · Cited by 1,141 · cited 9×
“Yet, the mechanisms by which mammalian cells recognize stress in order to initiate the ESR are still not fully understood.”
BackgroundMethodInfluentialDysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030420 · Cited by 1,060
Stress-activated cap’n’collar transcription factors in aging and human disease
Sykiotis, G. P., & Bohmann, D. (2010) · Science Signaling · doi:10.1126/scisignal.3112re3 · Cited by 776 · cited 1×
“The physiological significance of the ESR is profound; by minimizing cellular damage, it influences lifespan (3), plays a role in tumor suppression (4), and decreases susceptibility to degenerative diseases (5).”
BackgroundBosworth, C. A., Toledo, J. C., Zmijewski, J. W., Li, Q., & Lancaster, J. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710416106 · Cited by 220
NF‐E2‐related factor 2 regulates the stress response to UVA‐1‐oxidized phospholipids in skin cells
Gruber, F., Mayer, H., Lengauer, B., Mlitz, V., Sanders, J. M., Kadl, A., Bilban, M., de Martin, R., Wagner, O., Kensler, T. W., et al. (2010) · The FASEB Journal · doi:10.1096/fj.09-133520 · Cited by 80
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
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
Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1
Mills, E. L., Ryan, D. G., Prag, H. A., Dikovskaya, D., Menon, D., Zaslona, Z., Jedrychowski, M. P., Costa, A. S. H., Higgins, M., Hams, E., et al. (2018) · Nature · doi:10.1038/nature25986 · Cited by 1,885
NRF2, a Transcription Factor for Stress Response and Beyond
He, F., Ru, X., & Wen, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134777 · Cited by 1,820
NRF2 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
Metadata
- Authors
- McMahon, M., Lamont, D. J., Beattie, K. A., & Hayes, J. D.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2010-10-18
- Volume
- 107
- Issue
- 44
- Pages
- 18838-18843
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1966830269
- Cited by
- 443
- References
- 10
- FWCI
- 8.74
- Type
- journal article
- Language
- en
- Open access
- green
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