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The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction

Author

Listed:
  • Ahmad Luqman-Fatah

    (Kyoto University
    Kyoto University)

  • Yuzo Watanabe

    (Kyoto University)

  • Kazuko Uno

    (Louis Pasteur Center for Medical Research)

  • Fuyuki Ishikawa

    (Kyoto University
    Kyoto University)

  • John V. Moran

    (University of Michigan Medical School
    University of Michigan Medical School)

  • Tomoichiro Miyoshi

    (Kyoto University
    Kyoto University
    RIKEN Center for Integrative Medical Sciences)

Abstract

Some interferon stimulated genes (ISGs) encode proteins that inhibit LINE-1 (L1) retrotransposition. Here, we use immunoprecipitation followed by liquid chromatography-tandem mass spectrometry to identify proteins that associate with the L1 ORF1-encoded protein (ORF1p) in ribonucleoprotein particles. Three ISG proteins that interact with ORF1p inhibit retrotransposition: HECT and RLD domain containing E3 ubiquitin-protein ligase 5 (HERC5); 2′−5′-oligoadenylate synthetase-like (OASL); and helicase with zinc finger 2 (HELZ2). HERC5 destabilizes ORF1p, but does not affect its cellular localization. OASL impairs ORF1p cytoplasmic foci formation. HELZ2 recognizes sequences and/or structures within the L1 5′UTR to reduce L1 RNA, ORF1p, and ORF1p cytoplasmic foci levels. Overexpression of WT or reverse transcriptase-deficient L1s lead to a modest induction of IFN-α expression, which is abrogated upon HELZ2 overexpression. Notably, IFN-α expression is enhanced upon overexpression of an ORF1p RNA binding mutant, suggesting ORF1p binding might protect L1 RNA from “triggering” IFN-α induction. Thus, ISG proteins can inhibit retrotransposition by different mechanisms.

Suggested Citation

  • Ahmad Luqman-Fatah & Yuzo Watanabe & Kazuko Uno & Fuyuki Ishikawa & John V. Moran & Tomoichiro Miyoshi, 2023. "The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction," Nature Communications, Nature, vol. 14(1), pages 1-26, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35757-6
    DOI: 10.1038/s41467-022-35757-6
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