代謝産蛋白変異は,KEAP1-NRF2シグナル伝達と糖分解を統合する

Michael J Bollong¹, Gihoon Lee^2,3, John S Coukos^2,3

¹Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

Nature

|October 17, 2018

まとめ

酵素PGK1を阻害すると,反応性メチルグリオキサルが増加し,KEAP1が変化する. これはNRF2の抗酸化反応を活性化させ,細胞のストレス防御と糖分解を結びつける.

科学分野:

生物化学
分子生物学
細胞の代謝

背景:

細胞ホメオスタシスは,代謝状態と調節経路を統合することに依存しています.
反応性代謝物は,代謝や転写などの細胞機能に影響を及ぼし,タンパク質を共性的に修正することができる.
KEAP1は,NRF2媒介の抗酸化反応を調節する,反応性種のセンサーとして作用する.

研究の目的:

糖分解とNRF2シグナル伝達経路の間のリンクを特定する.
糖分解抑制が細胞のストレス反応に影響するメカニズムを調査する.
KEAP1-NRF2軸を標的とした治療戦略を探求する.

主な方法:

酵素リン酸キナーゼ1 (PGK1) を抑制する.
反応性代謝物質の蓄積,特にメチルグリオキサルの分析
KEAP1の共性変異とそのNRF2レベルと活性への影響の特徴.
NRF2媒介による転写活性化の評価

主要な成果:

PGK1の抑制はメチルグリオキサルの蓄積につながる.
メチルグリオキサルはKEAP1を選択的に変化させ,システインとアルギニンの残留物間のメチリミダゾールクロスリンク (MICA) を形成します.
KEAP1の修正は,その二分化,NRF2の蓄積,およびNRF2転写プログラムの活性化につながる.
糖分解とKEAP1-NRF2経路の間の直接的なコミュニケーションが示されています.

結論:

糖分解はKEAP1-NRF2の転写軸に直接影響を及ぼします.
KEAP1のメチルグリオキサルの媒介による変異は,細胞のストレス反応における重要な調節メカニズムである.
この経路は,抗酸化反応を含む疾患の潜在的な治療目標です.

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