HRG-9の同類型は,ヘム濃縮区画からのヘム取引を規制する

Fengxiu Sun¹, Zhenzhen Zhao¹, Mathilda M Willoughby²

¹MOE Key Laboratory of Biosystems Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

Nature

|October 19, 2022

まとめ

トランスポートとゴルジ組織2 (TANGO2) は,細胞内のヘム輸送を促進する重要なヘムチャペロンとして機能します. この発見はTANGO2に関連した疾患とその治療法についての洞察を提供します.

科学分野:

細胞生物学
分子生物学
遺伝学

背景:

ヘムは細胞機能に不可欠ですが,細胞内輸送と利用のメカニズムは完全に理解されていません.
ヘーム結合タンパク質はどこにでも存在し,ヘームの密輸経路を明らかにする必要性を強調しています.
ヘムホメオスタシスの不調は,様々な細胞および生理学的障害に関連しています.

研究の目的:

細胞内ヘム輸送を制御する分子機構を特定し,特徴づけること.
ヘーム反応性遺伝子9 (HRG-9) / トランスポートとゴルジ組織2 (TANGO2) のヘームホメオスタシスの役割を調査する.
TANGO2機能と人間のTANGO2に関連する代謝障害との関連を確立する.

主な方法:

ゲノムモデルを活用した. カエノラブディティス・エレガンズ,酵母,哺乳類の細胞,ゼブラフィッシュなど.
TANGO2とヘムの相互作用を評価するためにヘム結合試験を行った.
TANGO2欠乏モデルにおける細胞血液分布とタンパク質機能を分析した.
斑馬魚の幼虫におけるTANGO2欠乏の現象的な影響

主要な成果:

HRG-9 (TANGO2) は,合成/貯蔵場所からのヘム輸送を媒介する,進化的に保存されたヘムチャペロンとして機能する.
HRG-9/TANGO2の損失は,特定の臓器 (虫のリソソーム関連臓器,酵母/哺乳類の細胞のミトコンドリア) でヘム蓄積につながります.
TANGO2はヘムと直接結合し,アポヘモプロテインへの転送を促進し,TANGO2の欠乏はゼブラフィッシュで重度の発達障害を引き起こす.

結論:

HRG-9/TANGO2は,細胞内血流と血の恒常性を維持するために不可欠です.
この研究は,TANGO2に関連した代謝性脳症および心律不整症の分子基礎を提供する.
TANGO2機能をターゲットにすることで,TANGO2に関連する遺伝疾患の治療戦略を提供することができます.

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