piR-bmo-796514 facilitates the proliferation of exogenous DNA virus (baculovirus) by targeting the host E3 ubiquitin ligase RNF181.

PIWI-interacting RNAs (piRNAs), a class of 23-31 nucleotide non-coding RNAs, are known for silencing transposons and endogenous retroviruses that reside in animal genomes. However, the mechanisms by which host piRNAs affect exogenous viral infections, particularly those by DNA viruses, remain poorly understood. Here, we demonstrated that infection by Bombyx mori nucleopolyhedrovirus (BmNPV), a large DNA virus, induced significant upregulation of silkworm host piR-bmo-796514, which facilitated viral proliferation by suppressing the expression of E3 ubiquitin ligase RNF181. We further revealed that RNF181 exerted antiviral activity through ubiquitin-mediated degradation of Integrin α2b-like, a cellular membrane protein that interacted with viral GP64 protein to mediate BmNPV entry. This study unveiled a previously unrecognized regulatory axis connecting host derived piRNAs with exogenous DNA virus infection, providing further mechanistic insights into the modulation of exogenous viral pathogenesis through the reprogramming of the piRNA pathway. Our findings not only advance the understanding of the immune escape mechanism of exogenous viruses but also provide new insights for the development of oligonucleotide antiviral drugs that target proviral piRNAs.