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. 2022 Aug;608(7924):757-765.
doi: 10.1038/s41586-022-05054-9. Epub 2022 Aug 10.

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

Nenad Bartonicek  1   2 , Romain Rouet  1   3 , Joanna Warren  1 , Claudia Loetsch  1   3 , Gabriela Santos Rodriguez  1   3 , Stacey Walters  1   3 , Francis Lin  1 , David Zahra  1 , James Blackburn  1   2   3 , Jillian M Hammond  1 , Andre L M Reis  1   2 , Ira W Deveson  1   2   3 , Nathan Zammit  1   3 , Mahdi Zeraati  4 , Shane Grey  1   3 , Daniel Christ  1   3 , John S Mattick  1   4 , Tatyana Chtanova  1   4 , Robert Brink  1   3 , Marcel E Dinger  4 , Robert J Weatheritt  1   3 , Jonathan Sprent  1   3 , Cecile King  5   6
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The retroelement Lx9 puts a brake on the immune response to virus infection

Nenad Bartonicek et al. Nature. 2022 Aug.

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.

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