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Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response
Open accessAbstract
The Keap1-Nrf2 system plays a central role in cytoprotection against electrophilic/oxidative stresses. Although Cys151, Cys273, and Cys288 of Keap1 are major sensor cysteine residues for detecting these stresses, it has not been technically feasible to evaluate the functionality of Cys273 or Cys288, since Keap1 mutants that harbor substitutions in these residues and maintain the ability to repress Nrf2 accumulation do not exist. To overcome this problem, we systematically introduced amino acid substitutions into Cys273/Cys288 and finally identified Cys273Trp and Cys288Glu mutations that do not affect Keap1's ability to repress Nrf2 accumulation. Utilizing these Keap1 mutants, we generated stable murine embryonic fibroblast (MEF) cell lines and knock-in mouse lines. Our analyses with the MEFs and peritoneal macrophages from the knock-in mice revealed that three major cysteine residues, Cys151, Cys273, and Cys288, individually and/or redundantly act as sensors. Based on the functional necessity of these three cysteine residues, we categorized chemical inducers of Nrf2 into four classes. Class I and II utilizes Cys151 and Cys288, respectively, while class III requires all three residues (Cys151/Cys273/Cys288), while class IV inducers function independently of all three of these cysteine residues. This study thus demonstrates that Keap1 utilizes multiple cysteine residues specifically and/or collaboratively as sensors for the detection of a wide range of environmental stresses.
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“Most recently, an intriguing study in peritoneal tumours (B16 melanoma and ID8 ovarian carcinoma) has demonstrated that tumour-infiltrating macrophages release itaconate which potentiates tumour growth74.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [74]
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“Itaconate was shown to boost OXPHOS and mtROS generation and subsequent MAPK activation in tumour-infiltrating macrophages (Figure 3).”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [74]
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Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6943 · Cited by 3,999
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-citationWang, H., Yang, H., Shivalila, C. S., Dawlaty, M. M., Cheng, A. W., Zhang, F., & Jaenisch, R. (2013) · Cell · doi:10.1016/j.cell.2013.04.025 · Cited by 3,495
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
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Zhang, D. D., Lo, S., Cross, J. V., Templeton, D. J., & Hannink, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10941-10953.2004 · Cited by 1,284
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Suzuki, T., & Yamamoto, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.006 · Cited by 995
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Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., Takahashi, S., Imakado, S., KOTSUJI, T., Otsuka, F., Roop, D. R., et al. (2003) · Nature Genetics · doi:10.1038/ng1248 · Cited by 881
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Ohta, T., Iijima, K., Miyamoto, M., Nakahara, I., Tanaka, H., Ohtsuji, M., Suzuki, T., Kobayashi, A., Yokota, J., Sakiyama, T., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5003 · Cited by 630
Self-citationKang, M.-I., Kobayashi, A., Wakabayashi, N., Kim, S.-G., & Yamamoto, M. P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308347100 · Cited by 545
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Yamamoto, T., Suzuki, T., Kobayashi, A., Wakabayashi, J., Maher, J. M., Motohashi, H., & Yamamoto, M. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01704-07 · Cited by 515
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Tong, K. I., Padmanabhan, B., Kobayashi, A., Shang, C., Hirotsu, Y., Yokoyama, S., & Yamamoto, M. P. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00753-07 · Cited by 459
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Hong, F., Freeman, M. L., & Liebler, D. C. (2005) · Chemical Research in Toxicology · doi:10.1021/tx0502138 · Cited by 404
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Gao, L., Wang, J., Sekhar, K. R., Yin, H., Yared, N. F., Schneider, S. N., Sasi, S., Dalton, T. P., Anderson, M. E., Chan, J. Y., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m607622200 · Cited by 289
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Takaya, K., Suzuki, T., Motohashi, H., Onodera, K., Satomi, S., Kensler, T. W., & Yamamoto, M. P. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.06.023 · Cited by 284
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Cleasby, A., Yon, J. R., Day, P. J., Richardson, C. J., Tickle, I. J., Williams, P. A., Callahan, J. F., Carr, R. A. E., Concha, N. O., Kerns, J. K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098896 · Cited by 271
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Hourihan, J. M., Kenna, J. G., & Hayes, J. D. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4944 · Cited by 239
Ogura, T., Tong, K. I., Mio, K., Maruyama, Y., Kurokawa, H., Sato, C., & Yamamoto, M. P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914036107 · Cited by 232
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Kansanen, E., Bonacci, G., Schopfer, F. J., Kuosmanen, S. M., Tong, K. I., Leinonen, H., Woodcock, S. R., Yamamoto, M., Carlberg, C., Ylä-Herttuala, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.190710 · Cited by 208
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Eggler, A. L., Small, E., Hannink, M., & Mesecar, A. D. (2009) · Biochemical Journal · doi:10.1042/bj20090471 · Cited by 178
Fujii, S., Sawa, T., Ihara, H., Tong, K. I., Ida, T., Okamoto, T., Ahmed, K. A., Ishima, Y., Motohashi, H., Yamamoto, M. P., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.145441 · Cited by 152
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Metadata
- Authors
- Saito, R., Suzuki, T., Hiramoto, K., Asami, S., Naganuma, E., Suda, H., Iso, T., Yamamoto, H., Morita, M., Baird, L., Furusawa, Y., Negishi, T., Ichinose, M., & Yamamoto, M.
- Affiliations
- Tohoku University (JP)
- Mochida Pharmaceutical (Japan) (JP)
- Corresponding author
- Suzuki, Takafumi
- Yamamoto, Masayuki
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2016-01-01
- Volume
- 36
- Issue
- 2
- Pages
- 271-284
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC4719294
- OpenAlex
- W2202703189
- Cited by
- 294
- References
- 47
- Citations by year
- 2026: 30 · 2025: 30 · 2024: 23 · 2023: 26 · 2022: 36 · 2021: 21 · 2020: 48 · 2019: 24 · 2018: 28 · 2017: 14 · 2016: 14
- FWCI
- 8.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- P-DIRECT
- Ministry of Education, Culture, Sports, Science, and Technology (24249015, 26111002, 26460354, 25112502, 2611010)
- Takeda Science Foundation
- AMED-CREST, Japan Agency for Medical Research and Development
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- Keap1, Nrf2, oxidative stress, electrophilic stress, Nrf2 inducers, peritoneal macrophages, murine embryonic fibroblasts, cytoprotection
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Amino Acid Sequence, Animals, Cell Line, Cysteine, Cytoskeletal Proteins, Humans, Mice, Transgenic, Molecular Sequence Data, Mutation, Transfection, Sequence Alignment, Oxidative Stress, Amino Acid Substitution, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice, HEK293 Cells
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