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インターフェロン-αはDExHボックスヘリカーゼ58を刺激して肝細胞のフェロプトーシスを防ぐ

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Kai-Wei Jia1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of General Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China

    Translational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China

Ren-Qi Yao23,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Yi-Wen Fan1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Ding-Ji Zhang1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Ye Zhou1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Min-Jun Wang1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Li-Yuan Zhang1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Yue Dong1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Zhi-Xuan Li1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Su-Yuan Wang1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Mu Wang1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Yun-Hui Li1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Lu-Xin Zhang1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Ting Lei1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Liang-Chen Gui1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Shan Lu1,  
  • Affiliation：

    Center for Immunotherapy, Chinese Academy of Medical Sciences, Beijing 100005, China

Ying-Yun Yang4,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Si-Xian Wang1,  
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

Yi-Zhi Yu1,  
  • role： Corresponding author通信作者
  • Affiliation：

    Translational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China

  • Email：c_ff@sina.com
  • Introduction：*c_ff@sina.com;
Yong-Ming Yao3*,  
  • role： Corresponding author通信作者
  • Affiliation：

    National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai 200433, China

  • Email：houjin@immunol.org
  • Introduction：houjin@immunol.org
Jin Hou1*

サマリー

Background:Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family.Methods:The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep−/−. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS).Results:Excessive production of reactive oxygen species (ROS) decreased the expression of the interferon (IFN)-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the N6-methyladenosine (m6A) reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis.Conclusions:This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.

キーワード

Ischemia/reperfusion (I/R);DExH-box helicase 58 (DHX58);Glutathione peroxidase 4 (GPX4);N6-methyladenosine (m6A) modification;YT521-B homology domain containing 2 (YTHDC2)

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