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

## TL;DR

A host piRNA, piR-bmo-796514, helps a DNA virus spread by reducing an antiviral protein, RNF181, in silkworms.

## Contribution

First demonstration of a host piRNA promoting exogenous DNA virus proliferation by targeting an E3 ubiquitin ligase.

## Key findings

- piR-bmo-796514 suppresses RNF181, enabling BmNPV proliferation.
- RNF181 degrades Integrin α2b-like, a receptor for BmNPV entry.
- Host piRNA pathway can be reprogrammed to aid viral immune escape.

## Abstract

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.

In this study, utilizing the silkworm as a model organism, we have focused on a host derived piRNA, piR-bmo-796514, which was significantly induced by Bombyx mori nucleopolyhedrovirus (BmNPV) infection and could promote (rather than inhibit) the proliferation of exogenous DNA viruses. Importantly, our findings demonstrated that piR-bmo-796514 promoted BmNPV proliferation by suppressing the expression of the E3 ubiquitin ligase RNF181. Concurrently, we discovered that RNF181 exerted its antiviral function against BmNPV through the ubiquitination and subsequent degradation of the transmembrane receptor Integrin α2b-like, which interacted with the BmNPV GP64 envelope protein to facilitate viral entry. Taken together, our study unraveled for the first time the molecular mechanism by which a host-derived piRNA could mediate the immune escape response during infection of an exogenous DNA virus. Our study will promote further research on the functional mechanisms of specific host piRNAs during exogenous viral infection.