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

Bartoniček, Nenad; Rouet, Romain; Warren, Joanna; Loetsch, Claudia; Rodriguez, Gabriela Santos; Walters, Stacey N.; Lin, Francis; Zahra, David; Blackburn, James; Hammond, Jillian M.; Reis, André; Zammit, Nathan W.; Zeraati, Mahdi; Grey, Shane T.; Christ, Daniel; Mattick, John S.; Chtanova, Tatyana; Brink, Robert; Dinger, Marcel E.; Weatheritt, Robert J.; Sprent, Jonathan; King, Cecile

doi:10.1038/s41586-022-05054-9

Cited by 12 publications

(9 citation statements)

References 74 publications

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“…Recently, structurally similar SLFN-like proteins have been shown to help piRNA processing in C.elegans (Podvalnaya et al 2023). Thus, it is possible that orphan genes such as SLFNL1 might carry out ancestral functions in RNA biogenesis, perhaps related to retrotransposon control (Bartonicek et al 2022; Ding et al 2023; Podvalnaya et al 2023). If so, clustered SLFN antiviral functions might have arose following the addition of regulatory domains such as GTPase and Helicase domains to the “SCHLAFEN core”.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Evolutionary Innovations in Rodent and PrimateSchlafenGenes

Mordier,

Fraisse,

Cohen-Tannoudji

et al. 2024

Preprint

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SCHLAFEN proteins are a large family of RNase-related enzymes carrying essential immune and developmental functions. Despite these important roles, Schlafen genes display varying degrees of evolutionary conservation in mammals. While this appears to influence their molecular activities, a detailed understanding of these evolutionary innovations is still lacking. Here, we used in depth phylogenomic approaches to characterize the evolutionary trajectories and selective forces shaping mammalian Schlafen genes. We traced lineage-specific Schlafen amplifications and found that recent duplicates evolved under distinct selective forces, supporting repeated sub-functionalization cycles. Codon-level natural selection analyses in primates and rodents, identified recurrent positive selection over Schlafen protein domains engaged in viral interactions. Combining crystal structures with machine learning predictions, we discovered a novel class of rapidly evolving residues enriched at the contact interface of SCHLAFEN protein dimers. Our results suggest that inter Schlafen compatibilities are under strong selective pressures and are likely to impact their molecular functions. We posit that cycles of genetic conflicts with pathogens and between paralogs drove Schlafens' recurrent evolutionary innovations in mammals.

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Section: Discussionmentioning

confidence: 99%

Recurrent Evolutionary Innovations in Rodent and PrimateSchlafenGenes

Mordier,

Fraisse,

Cohen-Tannoudji

et al. 2024

Preprint

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“…Given that enzymatic activity of PUCH requires association of three different SLFN-domain containing subunits, one can hypothesize that in mice complexes between distinct paternal and maternal Slfn proteins may form active enzymes, whose activity, or lack thereof, may trigger embryonic lethality. Another study in mice showed that a transposon encoded non-coding RNA inhibits Slfn gene expression and thus prevents over-activity of the innate immune system in response to virus infection 47 . Moreover, in humans links between immunity and SLFN proteins are known.…”

Section: Discussionmentioning

confidence: 99%

piRNA processing by a trimeric Schlafen-domain nuclease

Podvalnaya¹,

Bronkhorst²,

Lichtenberger

et al. 2023

Preprint

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Transposable elements are genomic parasites that expand within and spread between genomes1. Piwi proteins control transposon activity, notably in the germline2,3. These proteins recognize their targets through small RNA co-factors named piRNAs, making piRNA biogenesis a key specificity-determining step in this crucial genome immunity system. While the processing of piRNA precursors is an essential step in this process, many molecular details of this process remain unknown. We identify a novel endoribonuclease, PUCH, that initiates piRNA processing in the nematode Caenorhabditis elegans. Genetic and biochemical studies show that PUCH, a trimer of Schlafen-like-domain proteins (SLFL proteins), executes 5-end piRNA precursor cleavage. PUCH-mediated processing strictly requires an m7G-Cap and a uracil at position three. We also demonstrate how PUCH interacts with PETISCO, a complex that binds piRNA precursors4, and that this interaction enhances piRNA production in vivo. The identification of PUCH completes the repertoire of C. elegans piRNA biogenesis factors and uncovers a novel type of RNA endonuclease formed by three SLFL proteins. Mammalian Schlafen (Slfn) genes have been associated with immunity responses5, exposing a thus far unknown molecular link between immune responses in mammals and deeply conserved RNA-based mechanisms that control transposable elements.

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“…Another demonstrated that an L1MC5 element within the intron of IFNGR2 acts as a cryptic splice acceptor in T cells, resulting in transcriptional repression [ 63 ]. Finally, in mice, an Lx9 element was demonstrated to be an essential long non-coding RNA that inhibits the immune response [ 19 ]. Our functional characterization of IFNAR2.L1M2a.enh in immune cells provides a key demonstration that LINEs can also be co-opted as inducible enhancers.…”

Section: Discussionmentioning

confidence: 99%

“…This tendency to truncate the regulatory elements, along with the targeted epigenetic repression of LINEs makes them a less obvious source of cis-regulatory enhancer activity, but studies have explored other mechanisms by which LINEs have been shown to regulate expression of host genes [ 16 ]. For instance, LINEs have been observed to regulate their host genes through transcriptional interference [ 14 , 18 ], as non-coding RNAs [ 19 ], and as a source of immunostimulatory RNA [ 20 – 22 ]. Multiple studies have predicted LINE enhancer activity based on epigenomic data [ 23 – 27 ], but their biological significance remains uncharacterized.…”

Section: Introductionmentioning

confidence: 99%

An intronic LINE-1 regulates IFNAR1 expression in human immune cells

Buttler,

Ramirez,

Dowell

et al. 2023

Mobile DNA

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Background Despite their origins as selfish parasitic sequences, some transposons in the human genome have been co-opted to serve as regulatory elements, contributing to the evolution of transcriptional networks. Most well-characterized examples of transposon-derived regulatory elements derive from endogenous retroviruses (ERVs), due to the intrinsic regulatory activity of proviral long terminal repeat regions. However, one subclass of transposable elements, the Long Interspersed Nuclear Elements (LINEs), have been largely overlooked in the search for functional regulatory transposons, and considered to be broadly epigenetically repressed. Results We examined the chromatin state of LINEs by analyzing epigenomic data from human immune cells. Many LINEs are marked by the repressive H3K9me3 modification, but a subset exhibits evidence of enhancer activity in human immune cells despite also showing evidence of epigenetic repression. We hypothesized that these competing forces of repressive and activating epigenetic marks might lead to inducible enhancer activity. We investigated a specific L1M2a element located within the first intron of Interferon Alpha/Beta Receptor 1 (IFNAR1). This element shows epigenetic signatures of B cell-specific enhancer activity, despite being repressed by the Human Silencing Hub (HUSH) complex. CRISPR deletion of the element in B lymphoblastoid cells revealed that the element acts as an enhancer that regulates both steady state and interferon-inducible expression of IFNAR1. Conclusions Our study experimentally demonstrates that an L1M2a element was co-opted to function as an interferon-inducible enhancer of IFNAR1, creating a feedback loop wherein IFNAR1 is transcriptionally upregulated by interferon signaling. This finding suggests that other LINEs may exhibit cryptic cell type-specific or context-dependent enhancer activity. LINEs have received less attention than ERVs in the effort to understand the contribution of transposons to the regulatory landscape of cellular genomes, but these are likely important, lineage-specific players in the rapid evolution of immune system regulatory networks and deserve further study.

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

Cited by 12 publications

References 74 publications

Recurrent Evolutionary Innovations in Rodent and PrimateSchlafenGenes

Recurrent Evolutionary Innovations in Rodent and PrimateSchlafenGenes

piRNA processing by a trimeric Schlafen-domain nuclease

An intronic LINE-1 regulates IFNAR1 expression in human immune cells

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