Multi-Proteomic Insights into Lysine Propionylation and Malonylation Remodeling in PRRSV-Infected Porcine Lungs

Porcine reproductive and respiratory syndrome virus is a major pathogen that causes massive economic losses in the global swine industry. Lysine propionylation and malonylation are metabolism-sensitive post-translational modifications, yet their coordinated regulatory roles during PRRSV pulmonary infection remain unknown. This study combined quantitative proteomics, propionylome and malonylome to characterize host molecular alterations between healthy and PRRSV-infected porcine lung tissues (three piglets per group). Quantitative proteomics identified 1467 significantly downregulated proteins and only 129 upregulated proteins, indicating a profound host protein shutoff during PRRSV pulmonary infection. The two acyl modifications displayed opposite regulatory patterns independent of global protein expression changes: 51 propionylation sites (24 proteins) were upregulated with only 1 downregulated, while 37 malonylation sites (30 proteins) were downregulated and only 5 upregulated. Functional enrichment and PPI network analysis revealed clear functional divergence: hyper-propionylated hub proteins were exclusively enriched in mitochondrial energy metabolism pathways, whereas hypo-malonylated core proteins were mainly involved in lipid metabolism and cell fate regulation. Integrated multi-omics analysis confirmed that protein expression and lysine acylation constitute two coordinated but independent regulatory layers, with histone H4 identified as a candidate target of competitive propionylation/malonylation. This work reports the comprehensive landscape of lysine propionylation and malonylation upon PRRSV infection, reveals a dual-PTM remodeling strategy for viral hijacking of host homeostasis, and provides candidate targets for future functional investigation and antiviral development.