# Baculovirus enhances arginine uptake and induces mitochondrial autophagy to promote viral proliferation

## TL;DR

This study shows how baculovirus manipulates host cells to increase arginine uptake and use mitochondrial autophagy to support its own replication.

## Contribution

The study reveals a novel mechanism by which baculovirus induces arginine transporter expression and mitochondrial autophagy to maintain amino acid homeostasis for viral proliferation.

## Key findings

- BmNPV induces the expression of the arginine transporter Slc7a6 to enhance arginine uptake in host cells.
- BmNPV triggers mitochondrial autophagy to supplement intracellular arginine levels for viral replication.
- The virus employs a dual strategy of external nutrient acquisition and autophagy-mediated amino acid replenishment to maintain amino acid homeostasis.

## Abstract

As obligatory intracellular parasites, viruses must rely on metabolic reprogramming of host cells to meet their replication needs. Baculovirus is an important biopesticide and a vector for the preparation of biological products. In addition, one of its representative species, Bombyx mori nucleopolyhedrovirus (BmNPV-Baculoviridae), also causes huge losses to the insect industry. In our previous study, amino acid metabolism has been found to play a crucial role in the BmNPV infection process. However, the mechanisms by which BmNPV reprograms host amino acid metabolism remains unclear. In fact, current insights in the importance of amino acid metabolism are limited to the impact of glutamine on viral infection. Therefore, unraveling the mechanism of amino acid metabolism reprogramming induced by baculovirus would advance this field of research to a great extent. In this study, targeted metabolomics revealed that the preferred amino acids of BmNPV budded virus (BV) include arginine, lysine, proline, isoleucine, histidine and others. In addition, most of the viral amino acids were found to be increased in the hemolymph of BmNPV infected silkworms at the later stage of infection, especially arginine, valine, phenylalanine and others. Furthermore, the importance of arginine for BmNPV proliferation was validated. Next, we confirmed that the expression of the arginine transporter Slc7a6 was strongly induced by BmNPV infection and that Slc7a6 could promote arginine uptake to support BmNPV proliferation in host cells. Moreover, using Slc7a6 knockout cells which eliminate extracellular arginine uptake, we confirmed that BmNPV could induce mitochondrial autophagy, thereby supplementing intracellular arginine and providing necessary amino acids for BmNPV proliferation. Overall, these findings support a model in which baculovirus (BmNPV) enhances the uptake of exogenous amino acids by inducing the expression of amino acid transporters and activating autophagy of organelles to maintain intracellular amino acid levels, thereby facilitating virus proliferation.

Baculovirus is an important biopesticide and a vector for the preparation of biological products. In addition, one of its representative species, Bombyx mori nucleopolyhedrovirus, also causes huge losses to the insect industry. However, the mechanisms by which BmNPV reprograms host amino acid metabolism remains unclear. Therefore, unraveling the mechanism of amino acid metabolism reprogramming induced by baculovirus would advance this field of research to a great extent. In this study, our findings revealed that the predominant amino acids of BmNPV budded virus include arginine, lysine and proline. In addition, most of the viral key amino acids were found to be increased in the hemolymph of BmNPV infected silkworms at the later stage of infection, especially arginine. Furthermore, the importance of arginine for BmNPV proliferation was validated. Next, we confirmed the molecular mechanism by which BmNPV supplements intracellular arginine levels to maintain virus replication through the induction of arginine transporter Slc7a6 expression and mitochondrial autophagy. Overall, our data support a model whereby baculoviruses establish an “exogenous uptake-endogenous supply” paradigm by synergistically enhancing external nutrient acquisition and activating autophagy-mediated amino acid replenishment. This dual mechanism maintains intracellular amino acid homeostasis to facilitate baculovirus proliferation. Moreover, it reveals the viral strategy of hijacking host amino acid transport and the cellular autophagy system for efficient amino acid exploitation, offering a new perspective on host-virus interactions.