2. Academic Validation
  3. Compensation for impaired sensing of selenoprotein deficiency by alternative cysteine residues in KEAP1

Compensation for impaired sensing of selenoprotein deficiency by alternative cysteine residues in KEAP1

  • Redox Biol. 2026 Jun 15:95:104263. doi: 10.1016/j.redox.2026.104263.
Miu Sato 1,  Takuya Iijima 1,  Takafumi Suzuki 2,  Masayuki Yamamoto 3
Affiliations

Affiliations

  • 1 Department of Biochemistry & Molecular Biology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Aoba-ku, 980-8573, Japan.
  • 2 Department of Biochemistry & Molecular Biology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Aoba-ku, 980-8573, Japan; Department of Biochemistry & Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Sendai, Aoba-ku, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, 2-1 Seiryo-machi, Sendai, Aoba-ku, 980-8573, Japan. Electronic address: [email protected].
  • 3 Department of Biochemistry & Molecular Biology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Aoba-ku, 980-8573, Japan; Department of Biochemistry & Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Sendai, Aoba-ku, 980-8573, Japan. Electronic address: [email protected].
PMID: 42308694 DOI: 10.1016/j.redox.2026.104263
Abstract

The Keap1-Nrf2 system is a master regulator of cellular defense against oxidative and electrophilic stresses. Cysteine residues within KEAP1 function as critical stress sensors. While KEAP1-Cys151 is a well-established sensor for electrophilic NRF2 activators, its contribution to the oxidative stress response remains unclear. Here, we investigated NRF2 activation in Cys151-deficient mice under hepatocyte-specific disruption of selenoprotein synthesis, a condition associated with profound redox imbalance. NRF2 activation and hepatic homeostasis were preserved in these mice, indicating that Cys151 is dispensable for sensing of selenoprotein deficiency. Conversely, loss of Cys226/Cys613-mediated sensing impaired NRF2 activation, leading to severe liver injury and lethality. Importantly, treatment with the Cys151-dependent electrophilic activator CDDO-Im restored NRF2 activity and improved survival in mice lacking functional Cys226/Cys613 sensing. Together, these findings demonstrate that individual KEAP1 cysteine residues have distinct functional roles in stress sensing, yet their signals converge on a common pathway to regulate NRF2 activation.

Keywords

Electrophile; KEAP1; NRF2; Selenoprotein deficiency; Stress sensor.

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