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Hypoxia regulates overall mRNA homeostasis by inducing Met1-linked linear ubiquitination of AGO2 in cancer cells

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  • Hailong Zhang

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Xian Zhao

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Yanmin Guo

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Ran Chen

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Jianfeng He

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Lian Li

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Zhe Qiang

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Qianqian Yang

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Xiaojia Liu

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Caihu Huang

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Runhui Lu

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Jiayu Fang

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Yingting Cao

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Jiayi Huang

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Yanli Wang

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Jian Huang

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Guo-Qiang Chen

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
    Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine)

  • Jinke Cheng

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine)

  • Jianxiu Yu

    (State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
    Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine)

Abstract

Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells. Mechanistically, hypoxia induces the interaction of AGO2 with LUBAC, the linear ubiquitin chain assembly complex, which co-localizes with miRNA-induced silencing complex and in turn catalyzes AGO2 occurring Met1-linked linear ubiquitination (M1-Ubi). A series of biochemical experiments reveal that M1-Ubi of AGO2 restrains miRNA-mediated gene silencing. Moreover, combination analyses of the AGO2-associated mRNA transcriptome by RIP-Seq and the mRNA transcriptome by RNA-Seq confirm that AGO2 M1-Ubi interferes miRNA-targeted mRNA recruiting to AGO2, and thereby facilitates accumulation of global mRNAs. By this mechanism, short-term hypoxia may protect overall mRNAs and enhances stress tolerance, whereas long-term hypoxia in tumor cells results in seriously changing the entire gene expression profile to drive cell malignant evolution.

Suggested Citation

  • Hailong Zhang & Xian Zhao & Yanmin Guo & Ran Chen & Jianfeng He & Lian Li & Zhe Qiang & Qianqian Yang & Xiaojia Liu & Caihu Huang & Runhui Lu & Jiayu Fang & Yingting Cao & Jiayi Huang & Yanli Wang & J, 2021. "Hypoxia regulates overall mRNA homeostasis by inducing Met1-linked linear ubiquitination of AGO2 in cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25739-5
    DOI: 10.1038/s41467-021-25739-5
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    Cited by:

    1. Yesheng Fu & Lei Li & Xin Zhang & Zhikang Deng & Ying Wu & Wenzhe Chen & Yuchen Liu & Shan He & Jian Wang & Yuping Xie & Zhiwei Tu & Yadi Lyu & Yange Wei & Shujie Wang & Chun-Ping Cui & Cui Hua Liu & , 2024. "Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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