Stress Sensor Mechanism by the Keap1-Nrf2 System

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15590
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Suzuki Takafumi 東北大学, 医学系研究科, 講師 (70508308)
• Research Collaborator: YAMAMOTO Masayuki ; ISO Tatsuro ; MURAMATSU Aki ; SAITO Ryota ; BAIRD Liam ; SUDA Hiromi ; MORITA Masanobu
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: Keap1 / Nrf2

Outline of Final Research Achievements

The Keap1-Nrf2 system plays a central role in the oxidative stress response, however the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking eleven cysteine residues retains the ability to target Nrf2 for degradation, but is unable to respond to cysteine-reactive Nrf2 inducers. Of the eleven mutated cysteine residues, we found that four are important for sensing hydrogen peroxide. Our analyses revealed that Keap1 utilizes the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. Importantly, this sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses.

Free Research Field

医化学

Academic Significance and Societal Importance of the Research Achievements

酸化ストレスに対する応答系の破綻は様々な疾患発症と密接に関わっている。このような疾患を未然に防ぐ目的で、細胞は環境ストレスに対して素早い応答で対応し、恒常性を維持している。ストレスセンサーKeap1は転写因子Nrf2の活性を制御し、酸化ストレス防御機構の中心的役割を担う鍵因子である。本研究はKeap1が酸化ストレスを感知してNrf2を制御する分子メカニズムの一端を明らかにした。