# Quantitative proteomic analysis identifies the unfolded protein response as a host pathway co-opted by ASFV to promote replication

## TL;DR

This study uses proteomics to show how the African swine fever virus hijacks a host cell pathway to replicate, offering new insights for potential treatments.

## Contribution

The study reveals the unfolded protein response as a host pathway co-opted by ASFV to promote replication, using multi-organ proteomic analysis.

## Key findings

- ASFV activates all three branches of the unfolded protein response (UPR) in vivo and in vitro to enhance replication.
- The viral protein D117L interacts with multiple UPR-related host proteins, directly triggering UPR activation.
- A proteomic landscape of ASFV infection across multiple organs was mapped, revealing conserved functional modules like innate immunity and inflammation.

## Abstract

African swine fever (ASF), caused by the African swine fever virus (ASFV), is a highly contagious disease that affects pigs, resulting in substantial economic losses in the global pig industry. A comprehensive understanding of viral-host protein interactions can facilitate the discovery of therapies for viral infection. In this study, we employ a 4D label-free quantitative proteomics approach to profile a comprehensive protein dynamics analysis in ASFV-infected pigs, identifying over 6,000 proteins across multiple organs. Our results reveal coordinated interorgan responses characterized by inflammatory activation and interferon signaling in defense against ASFV. The protein-protein interaction network analysis uncovers ASFV-induced functional modules, including the unfolded protein response (UPR), innate immune signaling, and inflammation, which are conserved across tissues. Notably, ASFV robustly activates all three branches of the UPR both in vivo and in vitro to promote viral replication. Furthermore, we identify that the virus-encoded protein D117L interacts with multiple UPR-related host proteins, thereby directly triggering UPR activation. Collectively, this study delineates the organ-specific proteomic landscape of ASFV infection, providing valuable insights into virus-host interactions and offering potential therapeutic targets for ASF.

African swine fever virus (ASFV) has caused severe consequences for the global pig industry. In this study, we conducted a multi-organ proteomic analysis using a 4D label-free quantitative proteomics approach and mapped the organ-specific proteomic landscape during ASFV infection. This work overcomes the limitations of most existing studies, which are primarily restricted to in vitro cell models and provide a more comprehensive understanding of ASFV infection and pathogenesis. Notably, the viral D117L protein is identified as a critical modulator of host cellular responses, directly subverting the unfolded protein response (UPR) pathway through specific interactions with host UPR-associated proteins. Collectively, our work lays the foundation for understanding the pathogenesis of ASFV, providing potential therapeutic strategies against African swine fever.