N6メチラデノシンRNA改変媒介による細胞代謝再配線がウイルスの複製を阻害する

Yang Liu^1,2, Yuling You¹, Zhike Lu³

¹National Key Laboratory of Medical Molecular Biology, Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.

Science (New York, N.Y.)

|August 24, 2019

まとめ

ウイルスの感染はRNA脱甲基酵素ALKBH5を阻害し,OGDHとイタコナート生成を減少させます. この代謝再プログラミングはウイルスの複製を抑制し感染症に対する新しい戦略を提供します

科学分野:

ウイルス学
メタボロミクス
エピジェネティクス

背景:

ウイルスの感染は宿主細胞の代謝を大きく変化させ,ウイルスの生存とクリアランスに影響を与えます.
ウイルスと宿主の代謝相互作用におけるN6-メチラデノシン (m6A) RNA変異の役割は,ほとんど未知のものである.

研究の目的:

ウイルスの感染中に m6A RNA 変異が宿主細胞の代謝を再プログラムする方法を調査する.
m6Aがウイルスの複製と宿主耐性に影響を与えるメカニズムを解明する.

主な方法:

ウイルス感染に対する反応としてRNA m6A 脱メチラーゼ ALKBH5の酵素活性を調べた.
アルファケトグルタレット脱水素酵素 (OGDH) のm6Aメチル化レベルを分析した.
測定されたOGDHタンパク質発現とイタコナート産生
Alkbh5欠乏したマウスを利用して,in vivoのウイルス耐性を評価した.

主要な成果:

ホスト細胞はウイルス感染時にALKBH5の活性を低下させ,OGDH mRNAのm6Aを増加させる.
OGDH mRNAの安定性とタンパク質濃度の低下が観察されました.
OGDHの減少は,ウイルスの複製に不可欠なイタコナート産生を減少させた.
Alkbh5 欠乏したマウスは,ウイルスの曝露に対する生まれつきの免疫反応から独立した抵抗性を示した.

結論:

m6A RNAの改変により,OGDH-イタコネート経路が低下し,ウイルスの複製を抑制する.
m6Aによる宿主細胞の代謝の再プログラムが重要な抗ウイルスメカニズムです.
OGDH-イタコネート経路をターゲットにすることで,ウイルス感染症に対する潜在的な治療戦略を提示します.

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