還元性ストレス反応の構造的基礎と制御

Andrew G Manford¹, Elijah L Mena¹, Karen Y Shih¹

¹Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA 94720, USA.

Cell

|September 25, 2021

まとめ

細胞はFNIP1タンパク質を分解することで,低活性酸素種 (ROS) の状態である還元性ストレスを管理します. この過程は亜鉛とBEXファミリータンパク質によって制御され,細胞の恒常性を維持します.

科学分野:

生物化学
細胞生物学
分子生物学

背景:

酸化性リン酸化はATPだけでなく,反応性酸素種 (ROS) も生成する.
還元性ストレスは ROSの減少で細胞の信号伝達が妨げられ癌,糖尿病,心筋病などの病気につながります
細胞はミトコンドリアのタンパク質FNIP1を分解して還元ストレスに対抗する.

研究の目的:

E3リガゼCUL2^FEM1Bが細胞のリドックス状態に基づいて標的FNIP1を結合するメカニズムを解明する.
細胞環境の変化に応じてこの相互作用がどのように調節されているかを理解する.

主な方法:

CUL2^FEM1BとFNIP1の相互作用を媒介する亜鉛の役割を調査した.
CUL2^FEM1BおよびBEXファミリータンパク質の効果を研究するために,遺伝子操作 (機能獲得変異,遺伝子消去) を利用した.
細胞ホメオスタシスに対するFNIP1のユビキティレーションと分解の影響を調べました.

主要な成果:

CUL2^FEM1Bは亜鉛を分子ブリッジとして利用し,還元性ストレス中に減少したFNIP1を選択的に結合します.
BEXファミリーのタンパク質は,偽基板阻害剤として作用し,FNIP1の普遍化を阻害し,早期の分解を防止します.
この亜鉛に依存する経路の破壊は,FEM1Bの変異またはBEXの消去によって,発達異常につながる.

結論:

CUL2^FEM1Bによる減少FNIP1の亜鉛依存的徴募は,減少ストレス管理の重要なメカニズムである.
BEXタンパク質は,FNIP1の分解を制御することによって,不必要なROSの蓄積を防止する重要な調節剤です.
この亜鉛に依存する還元性ストレス反応の緊密な調節は,細胞と生物の恒常性を維持するために不可欠です.

キーワード:

BEX2 について BEX3 について CUL2 について FEM1B についてミトコンドリア酸化性リン酸化反応性酸素種還元性ストレスユビキチン

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