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Gene Review

Keap1  -  kelch-like ECH-associated protein 1

Mus musculus

Synonyms: Cytosolic inhibitor of Nrf2, INRF2, INrf2, Inrf2, Kelch-like ECH-associated protein 1, ...
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Disease relevance of Keap1

  • A recombinant protein containing both the Kelch/DGR domain and the C-terminal region of mouse Keap1 was expressed in Escherichia coli, purified to near-homogeneity and crystallized by the sitting-drop vapour-diffusion method [1].
  • Furthermore, extensive studies have suggested that the Nrf2-Keap1 system contributes to protection against various pathologies, including carcinogenesis, liver toxicity, respiratory distress and inflammation [2].

High impact information on Keap1

  • When we ablated Keap1, Keap1-deficient mice died postnatally, probably from malnutrition resulting from hyperkeratosis in the esophagus and forestomach [3].
  • However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival [4].
  • We postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf2 nuclear shuttling mechanism [5].
  • Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain [5].
  • Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction [6].

Biological context of Keap1

  • Isothermal calorimetry analysis indicated that one Neh2 molecule interacts with two molecules of Keap1 via two binding sites, the stronger binding ETGE motif and the weaker binding DLG motif [7].
  • The results suggest that Nrf2-Keap1-dependent UGT1A1 induction by prooxidants might represent a key adaptive response to cellular oxidative stress that defends against a variety of environmental insults, including electrophile attacks and chemical carcinogenesis [8].
  • Keap1 acts both as a repressor of the Nrf2 transactivation and as a sensor of phase 2 inducers [9].
  • Inducers disrupt the cytoplasmic complex between the actin-bound protein Keap1 and the transcription factor Nrf2, thereby releasing Nrf2 to migrate to the nucleus where it activates the antioxidant response element (ARE) of phase 2 genes and accelerates their transcription [10].
  • Deletion and mutagenesis studies identified a nuclear export signal (NES) in the intervening region of Keap1 comprised of hydrophobic leucine and isoleucine residues in agreement with a traditional NES consensus sequence [11].

Anatomical context of Keap1

  • The Kelch/DGR (double-glycine repeat) domain of Keap1 associates with Nrf2 as well as with actin filaments [1].
  • The actin cytoskeleton therefore provides scaffolding that is essential for the function of Keap1, which is the sensor for oxidative and electrophilic stress [9].
  • Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway [12].
  • We also found constitutive Nrf2 nuclear accumulation in Keap1-deficient mouse macrophages [13].

Associations of Keap1 with chemical compounds

  • Chemical inducers such as sulforaphane are known to react with Keap1 cysteine residues, thereby promoting Nrf2 nuclear accumulation and hence ARE activation [14].
  • Inducers disrupt the Keap1-Nrf2 complex by modifying two (C273 and C288) of the 25 cysteine residues of Keap1 [15].
  • The most reactive residues of Keap1 (C(257), C(273), C(288), and C(297)) were identified by mapping the dexamethasone-modified cysteines by mass spectrometry of tryptic peptides [10].
  • Reporter cotransfection-transactivation analyses with a series of Keap1 deletion mutants revealed that in the absence of the double glycine repeat domain Keap1 does not bind to Nrf2 [9].
  • We hypothesized that oxidative and electrophilic stresses induce the nuclear accumulation of Nrf2 by affecting the Keap1-mediated rapid turnover of Nrf2, since such accumulation was diminished by the protein synthesis inhibitor cycloheximide [16].

Regulatory relationships of Keap1

  • Nrf2 is a key regulator of many detoxifying enzyme genes, and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions [17].

Other interactions of Keap1

  • Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model [7].
  • In conclusion, GSH depletion alone is insufficient for Nrf2 activation: a more direct interaction is required, possibly involving chemical modification of Nrf2 or Keap1, which is facilitated by the prior loss of GSH [18].
  • Purification, crystallization and preliminary X-ray diffraction analysis of the Kelch-like motif region of mouse Keap1 [1].
  • Induction of the phase 2 response, a major cellular reaction to oxidative/electrophile stress depends on a protein triad: actin-tethered Keap1 that binds to Nrf2 [19].
  • We propose that Keap1 is a component of a novel E3 ubiquitin ligase complex that is specifically targeted for inhibition by both chemopreventive agents and oxidative stress [20].
  • These results led to the conclusion that prothymosin-alpha-mediated nuclear import of INrf2/Cul3 Rbx1 complex leads to ubiquitination and degradation of Nrf2 inside the nucleus presumably to regulate nuclear level of Nrf2 and rapidly switch off the activation of Nrf2 downstream gene expression [21].

Analytical, diagnostic and therapeutic context of Keap1

  • Nuclear magnetic resonance titration study showed that these two motifs of the Neh2 domain bind to an overlapping site on the bottom surface of the beta-propeller structure of Keap1 [7].
  • Evidence for formation of such dimers was obtained by 2D PAGE of extracts of cells treated with inducers, and by the demonstration that whereas C273A and C288A mutants of Keap1 alone could not repress Nrf2 activation of the ARE-luciferase reporter, an equal mixture of these mutant constructs restored repressor activity [15].
  • Microarray analysis revealed that, while many detoxifying enzyme genes are highly expressed, some of the typical Nrf2-dependent genes are only marginally increased in the Keap1-deficient liver [17].
  • Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers [22].


  1. Purification, crystallization and preliminary X-ray diffraction analysis of the Kelch-like motif region of mouse Keap1. Padmanabhan, B., Scharlock, M., Tong, K.I., Nakamura, Y., Kang, M.I., Kobayashi, A., Matsumoto, T., Tanaka, A., Yamamoto, M., Yokoyama, S. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2005) [Pubmed]
  2. Nrf2-Keap1 defines a physiologically important stress response mechanism. Motohashi, H., Yamamoto, M. Trends in molecular medicine. (2004) [Pubmed]
  3. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., Takahashi, S., Imakado, S., Kotsuji, T., Otsuka, F., Roop, D.R., Harada, T., Engel, J.D., Yamamoto, M. Nat. Genet. (2003) [Pubmed]
  4. Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway. Kensler, T.W., Wakabayashi, N., Biswal, S. Annu. Rev. Pharmacol. Toxicol. (2007) [Pubmed]
  5. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J.D., Yamamoto, M. Genes Dev. (1999) [Pubmed]
  6. Structural 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. Mol. Cell (2006) [Pubmed]
  7. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Tong, K.I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., Yamamoto, M. Mol. Cell. Biol. (2006) [Pubmed]
  8. Nrf2-Keap1 Signaling Pathway Regulates Human UGT1A1 Expression in Vitro and in Transgenic UGT1 Mice. Yueh, M.F., Tukey, R.H. J. Biol. Chem. (2007) [Pubmed]
  9. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Kang, M.I., Kobayashi, A., Wakabayashi, N., Kim, S.G., Yamamoto, M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  11. Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Velichkova, M., Hasson, T. Mol. Cell. Biol. (2005) [Pubmed]
  12. Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Motohashi, H., Katsuoka, F., Engel, J.D., Yamamoto, M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  13. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., O'Connor, T., Yamamoto, M. Genes Cells (2003) [Pubmed]
  14. Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Eggler, A.L., Liu, G., Pezzuto, J.M., van Breemen, R.B., Mesecar, A.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  15. Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Wakabayashi, N., Dinkova-Kostova, A.T., Holtzclaw, W.D., Kang, M.I., Kobayashi, A., Yamamoto, M., Kensler, T.W., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  16. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Kobayashi, A., Kang, M.I., Watai, Y., Tong, K.I., Shibata, T., Uchida, K., Yamamoto, M. Mol. Cell. Biol. (2006) [Pubmed]
  17. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Okawa, H., Motohashi, H., Kobayashi, A., Aburatani, H., Kensler, T.W., Yamamoto, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  18. Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Goldring, C.E., Kitteringham, N.R., Elsby, R., Randle, L.E., Clement, Y.N., Williams, D.P., McMahon, M., Hayes, J.D., Itoh, K., Yamamoto, M., Park, B.K. Hepatology (2004) [Pubmed]
  19. Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Dinkova-Kostova, A.T., Holtzclaw, W.D., Wakabayashi, N. Biochemistry (2005) [Pubmed]
  20. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Zhang, D.D., Hannink, M. Mol. Cell. Biol. (2003) [Pubmed]
  21. Prothymosin-alpha mediates nuclear import of the INrf2/Cul3 Rbx1 complex to degrade nuclear Nrf2. Niture, S.K., Jaiswal, A.K. J. Biol. Chem. (2009) [Pubmed]
  22. Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers. Kwak, M.K., Wakabayashi, N., Kensler, T.W. Mutat. Res. (2004) [Pubmed]
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