Inactivation of Peroxiredoxin 6 by the Pla Protease of Yersinia pestis
Pneumonic plague represents the most severe form of disease caused byYersinia pestisdue to its ease of transmission, rapid progression, and high mortality rate. TheY. pestisouter membrane Pla protease is essential for the development of pneumonic plague; however, the complete repertoire of substrates cleaved by Pla in the lungs is not known. In this study, we describe a proteomic screen to identify host proteins contained within the bronchoalveolar lavage fluid of mice that are cleaved and/or processed byY. pestisin a Pla-dependent manner. We identified peroxiredoxin 6 (Prdx6), a host factor that contributes to pulmonary surfactant metabolism and lung defense against oxidative stress, as a previously unknown substrate of Pla. Pla cleaves Prdx6 at three distinct sites, and these cleavages disrupt both the peroxidase and phospholipase A2activities of Prdx6. In addition, we found that infection with wild-typeY. pestisreduces the abundance of extracellular Prdx6 in the lungs compared to that after infection with ΔplaY. pestis, suggesting that Pla cleaves Prdx6 in the pulmonary compartment. However, following infection with either wild-type or Δpla Y. pestis, Prdx6-deficient mice exhibit no differences in bacterial burden, host immune response, or lung damage from wild-type mice. Thus, while Pla is able to disrupt Prdx6 functionin vitroand reduce Prdx6 levelsin vivo, the cleavage of Prdx6 has little detectable impact on the progression or outcome of pneumonic plague.