# A novel SO2 probe inhibits lysophagy induced by Senecavirus A infection by promoting LAMP1 Cys375 sulfenylation

## TL;DR

A new SO2 probe inhibits lysophagy caused by Senecavirus A infection by modifying a key lysosomal protein, offering a potential antiviral strategy.

## Contribution

A novel SO2 probe (DLC) is introduced that inhibits lysophagy by promoting sulfenylation of LAMP1 at Cys375.

## Key findings

- Senecavirus A (SVA) infection reduces LAMP1 and induces lysophagy.
- DLC inhibits LAMP1 degradation and suppresses SVA replication by enhancing sulfenylation.
- DLC shows antiviral effects in both cell and mouse models.

## Abstract

Lysophagy plays a key role in maintaining autophagy homeostasis, but the induction and regulation mechanisms of lysophagy are not clear. In this study, we found that Senecavirus A (SVA) dramatically decreased lysosomal-associated membrane protein 1(LAMP1), significantly increased lysosomal permeability, and induced lysophagy. We demonstrated that the SO2 probe (2-(4-(dimethylamino-) phenyl)1,1, 3-trimethyl-1h-benzo [e] indole-3-ium, DLC) could inhibited the degradation of LAMP1 and reduced lysophagy caused by SVA infection. DLC directly binds to LAMP1, and enhanced sulfenylation modification of LAMP1 at Cys375 to inhibit non-lysine ubiquitination. Finally, we verified the antiviral effects of DLC in cells and in BALB/c mice. Taken together, our study lays the foundation for the identification of SVA infection targets and the development of antiviral drugs in the future.

Research has shown that SVA infection can induce autophagy to facilitate its own replication, but the specific type of autophagy activated remains unclear. We found that SVA infection led to the degradation of the lysosomal membrane protein LAMP1. Following lysosomal damage, lysophagy was activated to clear the impaired lysosomes. Here, we identified a novel antiviral small molecule, DLC, and through a series of experiments, revealed that DLC inhibits lysophagy and suppresses SVA replication by enhancing sulfinylation modification mediated by the gas signaling molecule SO2, thereby regulating the sulfinylation-ubiquitination balance. This study aims to fill the gap in understanding how SVA manipulates the lysophagy pathway and may provide potential targets for developing novel lysosome-targeting anti-SVA drugs, holding significant scientific implications.