is an important pathogenic bacterium of domestic animals. However, the mechanisms of infection are still poorly understood. Here, we found that was dramatically up-regulated in infected mice among 67 predicted lipoproteins of serotype A CQ2 strain (PmCQ2). To explore the role of in virulence and the potential of the mutant as a vaccine, mutant of PmCQ2 was successfully constructed. Then, the virulence characteristics, immune/inflammatory responses, and the survival rates of challenged mice were determined. As a result, it was found that the deletion of PmCQ2 significantly decreased bacterial loads and inflammatory responses of lung tissue in mice, resulting in improved survival. Mechanically, affects PmCQ2 capsular and lipopolysaccharide (LPS) synthesis and iron utilization-related genes expression affecting adhesion and phagocytosis. Furthermore, PM0442 bound directly to Toll-like receptor 2 (TLR2) to mediate the secretion of pro-inflammatory cytokine (IL-1β, TNF-α, IL-6, and IL-12p40) in macrophages via activation of the NF-κB, ERK1/2 and p38 signaling pathways. Notably, PmCQ2Δ0442 could provide 70-80% protection to mice challenged with 3.08 × 10 CFU of PmCQ2. Our findings demonstrate that is a virulence-related gene of PmCQ2, which provides new guidance for the prevention and control of Pasteurellosis.