Direct cell-to-cell transmission of retrotransposons
Posted on: 21 May 2025
Preprint posted on 15 March 2025
Blurring the lines between retrotransposons & viruses! sORF2 enables envelope-independent, direct cell-to-cell transmission of retrotransposons in Drosophila, challenging our understanding of mobile genetic elements.
Selected by Ally Simpson, Alyss Humphrey, UofA IMB565
Categories: genetics, immunology, microbiology
Background
Vertebrate endogenous retroviruses (ERVs) are remnants of ancient retroviral infections that are integrated into the host genome. They are often associated with transposable elements, particularly long terminal repeats (LTR) retrotransposons, and are considered prehistoric sequences. Most ERVs are defective, containing incomplete viral genomes that are noninfectious or replication-incompetent (Benkel, 1999). However, recent research has shown a few complete ERVs that can direct the production of infectious viral particles.
The fruit fly, Drosophila melanogaster, is an excellent model for studying endogenous retroviruses because its genome provides an abundance of young, diverse, and active ERVs. Certain key structural and functional features are conserved between insect and vertebrate ERVs, even though they are phylogenetically distinct. Such conserved elements include the canonical retroviral organization of gag, pol, and env genes flanked by two LTRs. However, many insect LTR retrotransposons lack a functional env gene which is believed to be required for cell-to-cell infectivity.
The host defense system suppresses insect ERVs and LTR retrotransposons through the PIWI/piRNA pathway, which is present within the Drosophila gonad. Active insect ERVs and LTR retrotransposons are expressed when the PIWI/piRNA pathway is disrupted, providing an opportunity to investigate their native biology. In this preprint, Voichek and colleagues focus on understanding ancestral LTR retrotransposons in insects and whether they have gained viral-like cell-to-cell transmission capability. Their findings reveal an environment-independent transmission mechanism that enables a group of LTR retrotransposons to enter oocytes directly from neighboring somatic cells.
Key Findings
This study uncovers a novel, envelope (env)-independent mechanism of retrotransposon transmission in Drosophila melanogaster by identifying a small transmembrane protein, sORF2, that facilitates the direct transfer of retrotransposon particles from soma to germline. Using a combination of genetic manipulations, RNA sequencing, smFISH, proteomics, and high-resolution microscopy, the authors systematically investigated LTR retrotransposons under conditions where the piRNA pathway is deficient and no longer suppresses transposon activity. This revealed that a specific clade of Metaviridae retrotransposons, the MDG1 group, including 412 and Stalker2, is strongly derepressed in somatic follicle cells despite lacking an env gene—unlike their Gypsy relatives.
To determine whether the MDG1 group of retrotransposons could infect the germline, the authors tracked the RNA of retrotransposons and Gag proteins. They found them accumulating at the apical membrane of somatic cells and entering the oocyte, suggesting active cell-to-cell transmission. Notably, they identified two short open reading frames (sORF1 and sORF2) upstream of the gag gene, with sORF2 encoding a 70–100 amino acid transmembrane protein. Using long-read RNA sequencing, untargeted proteomics, and custom antibodies, they confirmed that sORF2 is expressed, membrane-localized, and co-localizes with retrotransposon capsids at somatic protrusions targeting the oocyte. sORF2 contains hallmarks of fusogenic proteins, including a transmembrane domain, an N-terminal myristoylation motif, and amphipathic/polybasic regions—structural features strikingly similar to FAST (fusion-associated small transmembrane) proteins—which mediate cell-cell fusion in non-enveloped viruses. Electron microscopy revealed that sORF2 and capsids accumulate in actin-rich, invasive protrusions that extend into the oocyte, forming what the authors describe as fusogenic synapses, which enable the direct delivery of retrotransposon particles.
Through sequence and structural analyses, the authors demonstrate that sORF2/FAST-like proteins are evolutionarily conserved, with homologs found in insect retrotransposons, nakednaviruses (non-enveloped hepatitis B-like viruses in fish), and avian picornaviruses. This suggests that envelope-independent, cell-cell transmission mechanisms are ancient and widespread. These findings blur the lines between viruses and retrotransposons, highlighting a previously unrecognized evolutionary strategy for horizontal and vertical genetic transmission. By identifying a noncanonical, protein-mediated mechanism of transposon infectivity, this work reshapes our understanding of retrotransposon mobility, soma-germline interactions, and the molecular innovations that allow mobile genetic elements to persist and spread. It also opens new avenues for applying sORF2-like proteins in gene delivery and biotechnology, where viral machinery is often a limiting factor.
Figure 4I- sORF2 proteins resemble FAST proteins and promote cell fusion by facilitating the proximity of membranes
This is a proposed model for how MDG1 LTR retrotransposons spread from somatic cells to oocytes. (left) Special proteins (sORF2, shown in cyan) in somatic cells attach to retrotransposon capsids (pink). When enough of these proteins gather and other unknown signals occur, they trigger changes in the cell’s structure (green) (right). This causes the cell to form extensions that reach toward the oocyte. As these structures grow, the two membranes get close enough to create a connection that allows the retrotransposons to transfer. Image made available under a CC-BY 4.0 International license.
What we like about this preprint
Using RNA-seq and the piRNA source locus of the piRNA pathway, the authors were able to examine evolutionary connections between sORF2-containing elements across vertebrate and nonvertebrate species. Although this study initially focused on ERV’s ancient origins and functions, the authors were able to form a basis for a noncanonical cell-to-cell infectivity mechanism that highlights the adaptation and diversity of tasks among viral elements and transposons.
Studies like this one exemplify the power of a cross-organism approach. Despite differences among vertebrate and insect ERVs, this study highlights the degree of functional and even molecular convergence of transposable elements (TEs) in different genomes. Through the use of a range of different methods, the authors were able to support their findings for sORF2/FAST-like proteins.
Questions for the authors:
- Do you plan on doing future research on sORF2 with HBV, or will you mainly focus on viruses infecting insect species?
- You mention that the search criteria for sORF2/FAST-like proteins only focus on canonical start codons and N-terminal myristoylation motifs. How do you plan to address this limitation?
- What specific structural features of sORF2 make it functionally similar to viral fusogens?
- How might these findings contribute to our understanding of human endogenous retroviruses (HERVs) and their impact on the human genome?
Reference
Bernhard F. Benkel, ENDOGENOUS VIRUSES, Editor(s): Allan Granoff, Robert G. Webster, Encyclopedia of Virology (Second Edition), Elsevier, 1999, Pages 437-441, ISBN 9780122270307, https://doi.org/10.1006/rwvi.1999.0078. (https://www.sciencedirect.com/science/article/pii/B0122270304000789)
doi: https://doi.org/10.1242/prelights.40532
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