The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction
- PMID: 36639706
- PMCID: PMC9839780
- DOI: 10.1038/s41467-022-35757-6
The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction
Erratum in
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Author Correction: The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction.Nat Commun. 2023 Jan 30;14(1):493. doi: 10.1038/s41467-023-36226-4. Nat Commun. 2023. PMID: 36717557 Free PMC article. No abstract available.
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.
© 2023. The Author(s).
Conflict of interest statement
J.V.M. is an inventor on patent US6150160, is a paid consultant for Gilead Sciences, serves on the scientific advisory board to Tessera Therapeutics Inc. (where he is paid as a consultant and has equity options), has licensed reagents to Merck Pharmaceutical, and recently served on the American Society of Human Genetics Board of Directors. The other authors declare no competing interests.
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