The retroelement Lx9 puts a brake on the immune response to virus infection

Nenad Bartonicek, Romain Rouet, Joanna Warren, Claudia Loetsch, Gabriela Santos Rodriguez, Stacey Walters, Francis Lin, David Zahra, James Blackburn, Jillian M. Hammond, Andre L. M. Reis, Ira W. Deveson, Nathan Zammit, Mahdi Zeraati, Shane Grey, Daniel Christ, John S. Mattick, Tatyana Chtanova, Robert Brink, Marcel E. Dinger, Robert J. Weatheritt, Jonathan Sprent and Cecile King ()
Additional contact information
Nenad Bartonicek: The Garvan Institute of Medical Research
Romain Rouet: The Garvan Institute of Medical Research
Joanna Warren: The Garvan Institute of Medical Research
Claudia Loetsch: The Garvan Institute of Medical Research
Gabriela Santos Rodriguez: The Garvan Institute of Medical Research
Stacey Walters: The Garvan Institute of Medical Research
Francis Lin: The Garvan Institute of Medical Research
David Zahra: The Garvan Institute of Medical Research
James Blackburn: The Garvan Institute of Medical Research
Jillian M. Hammond: The Garvan Institute of Medical Research
Andre L. M. Reis: The Garvan Institute of Medical Research
Ira W. Deveson: The Garvan Institute of Medical Research
Nathan Zammit: The Garvan Institute of Medical Research
Mahdi Zeraati: UNSW Sydney
Shane Grey: The Garvan Institute of Medical Research
Daniel Christ: The Garvan Institute of Medical Research
John S. Mattick: The Garvan Institute of Medical Research
Tatyana Chtanova: The Garvan Institute of Medical Research
Robert Brink: The Garvan Institute of Medical Research
Marcel E. Dinger: UNSW Sydney
Robert J. Weatheritt: The Garvan Institute of Medical Research
Jonathan Sprent: The Garvan Institute of Medical Research
Cecile King: The Garvan Institute of Medical Research

Nature, 2022, vol. 608, issue 7924, 757-765

Abstract: Abstract The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago1,2. However, it was not until the advancement of genomic sequencing technologies that the abundance and repertoire of transposable elements were revealed, and they are now known to constitute up to two-thirds of mammalian genomes3,4. The presence of DNA regulatory regions including promoters, enhancers and transcription-factor-binding sites within transposable elements5–8 has led to the hypothesis that transposable elements have been co-opted to regulate mammalian gene expression and cell phenotype8–14. Mammalian transposable elements include recent acquisitions and ancient transposable elements that have been maintained in the genome over evolutionary time. The presence of ancient conserved transposable elements correlates positively with the likelihood of a regulatory function, but functional validation remains an essential step to identify transposable element insertions that have a positive effect on fitness. Here we show that CRISPR–Cas9-mediated deletion of a transposable element—namely the LINE-1 retrotransposon Lx9c11—in mice results in an exaggerated and lethal immune response to virus infection. Lx9c11 is critical for the neogenesis of a non-coding RNA (Lx9c11-RegoS) that regulates genes of the Schlafen family, reduces the hyperinflammatory phenotype and rescues lethality in virus-infected Lx9c11−/− mice. These findings provide evidence that a transposable element can control the immune system to favour host survival during virus infection.

Date: 2022
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DOI: 10.1038/s41586-022-05054-9

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