4.6 Article

Retrotransposon LINE-1 bodies in the cytoplasm of piRNA-deficient mouse spermatocytes: Ribonucleoproteins overcoming the integrated stress response

Journal

PLOS GENETICS
Volume 19, Issue 6, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1010797

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Although animals have developed TE-targeting defenses, LINE-1 still thrives in humans and mice. ORF1p interacts with TE RNAs, genic mRNAs, and stress granule proteins. ORF1p also associates with the CCR4-NOT deadenylation complex and PRKRA, without affecting the stability and translation of LB-localized mRNAs. The study shows that PRKRA elevates ORF1p levels and LINE-1 retrotransposition.
Transposable elements (TE) are mobile DNA sequences whose excessive proliferation endangers the host. Although animals have evolved robust TE-targeting defenses, including Piwi-interacting (pi)RNAs, retrotransposon LINE-1 (L1) still thrives in humans and mice. To gain insights into L1 endurance, we characterized L1 Bodies (LBs) and ORF1p complexes in germ cells of piRNA-deficient Maelstrom null mice. We report that ORF1p interacts with TE RNAs, genic mRNAs, and stress granule proteins, consistent with earlier studies. We also show that ORF1p associates with the CCR4-NOT deadenylation complex and PRKRA, a Protein Kinase R factor. Despite ORF1p interactions with these negative regulators of RNA expression, the stability and translation of LB-localized mRNAs remain unchanged. To scrutinize these findings, we studied the effects of PRKRA on L1 in cultured cells and showed that it elevates ORF1p levels and L1 retrotransposition. These results suggest that ORF1p-driven condensates promote L1 propagation, without affecting the metabolism of endogenous RNAs. Author summaryTransposable elements (TEs) are mobile DNA sequences whose proliferation endangers the integrity of the host cell and its genome. Although cells have acquired sophisticated TE-targeting defenses, TEs continue to thrive in all life forms. To address this fascinating question, this study focused on a particular type of TE known as retrotransposon LINE-1. This work shows that LINE-1-expressing germ cells of mice develop cytoplasmic aggregates (LINE-1 bodies or LBs) enriched in LINE-1, RNAs, and proteins implicated in the negative regulation of RNA expression. Despite the overwhelming repressive nature of LBs, the integrity and translation of LB-localized RNAs are not affected. RNA expression appears to stay intact because LINE-1 has adapted to interact with the PRKRA protein that relays stress signals to downstream proteins, triggering general translational inhibition. Indeed, the simultaneous expression of LINE-1 and PRKRA in cultured cells elevates LINE-1 protein expression and mobilization. Our data suggest that LINE-1 has evolved a mechanism to counteract the translational shut-off, thus increasing its chances of propagation without compromising the host cell.

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