Antisense Piwi-interacting RNAs (piRNAs) protect the germline genome from insertion-mediated mutation and instability by silencing established transposons. However, what prevents invasion by mobile elements in the first place has remained largely unknown. Now, a study in Cell shows that production of sense-strand piRNAs may have a pivotal role in this process.
An epidemic of KORV-A, a gammaretrovirus that infects the soma and germline of wild koalas, provided an ideal opportunity to study the germline response to retroviral invasion. Analysis of piRNAs mapping to established retrotransposons in the koala germline genome revealed similar levels of sense- and antisense-strand piRNAs. This result is consistent with the mechanism used to silence established transposons in the germline of other mammals, in which sense-strand piRNAs template ping-pong amplification of target-silencing antisense piRNAs. By contrast, predominantly sense-strand piRNAs mapped to KORV-A, suggesting that different mechanisms are used to suppress new versus established retroviral germline insertions.
The KORV-A provirus produces two transcripts: a spliced transcript that encodes the Env protein and an unspliced transcript that encodes the viral genome and the Gag and Pol proteins. Analysis of the distribution of KORV-A piRNAs at introns, exons, splice sites and exon–exon boundaries strongly suggests that the piRNA machinery preferentially processes and cuts unspliced KORV-A transcripts into sense-strand piRNAs. Removal of these transcripts (and the functions they encode) suppresses the ability of the virus to replicate and transpose.
The authors propose that this sense-strand piRNA-mediated suppression is analogous to the innate phase of the cellular immune response. During initial retroviral infection, a ‘pattern’ specific to unspliced proviral transcripts triggers an innate genome immune response. This response rids the germ cells of viral transcripts by processing them into sense-strand piRNAs and protects the genome from mass invasion.
the piRNA machinery preferentially processes and cuts unspliced KORV-A transcripts into sense-strand piRNAs
Moving forwards, it will be important to identify the precise nature of the pattern that activates the innate genome immune system. The authors speculate that persistent introns or poorly translated transcripts could be the trigger, but further studies will be needed to test these hypotheses.
Yu, T. et al. The piRNA response to retroviral invasion of the Koala genome. Cell https://doi.org/10.1016/j.cell.2019.09.002 (2019)
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Clyde, D. piRNAs make sense of retroviral invaders. Nat Rev Genet 20, 704 (2019). https://doi.org/10.1038/s41576-019-0187-2