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

• Published in: Nature communications Vol. 14; no. 1; pp. 203 - 26
• Main Authors: Luqman-Fatah, Ahmad, Watanabe, Yuzo, Uno, Kazuko, Ishikawa, Fuyuki, Moran, John V., Miyoshi, Tomoichiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/21; 13/31; 13/89; 14/35; 14/63; 38/1; 38/44; 38/88; 38/90; 5' Untranslated Regions; 631/208/211; 631/250/262; 631/337/1645; 82/1; 82/58; 82/83; Binding; DNA helicase; Genes; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunoprecipitation; Innate immunity; Interferon; Interferon Type I - genetics; Liquid chromatography; Localization; Long Interspersed Nucleotide Elements - genetics; Mass spectrometry; Mass spectroscopy; multidisciplinary; Proteins; Proteins - genetics; Proteomics; Retrotransposition; Ribonucleic acid; RNA; RNA - genetics; RNA Helicases - genetics; RNA-directed DNA polymerase; RNA-Directed DNA Polymerase - genetics; Science; Science (multidisciplinary); Ubiquitin; Ubiquitin-protein ligase; Zinc finger proteins; α-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35757-6

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. Proteomic analyses revealed that a group of interferon-stimulated genes suppresses LINE-1 retrotransposon activities, including HELZ2, which reduces LINE-1 RNA and the associated innate immune response levels.