Department of Biology, University of Texas Arlington, Arlington, Texas, United States of America.
PLoS Pathog. 2020 Sep 30;16(9):e1008918. doi: 10.1371/journal.ppat.1008918. eCollection 2020 Sep.
The mitochondrial unfolded protein response (UPRmt) is a stress-activated pathway promoting mitochondrial recovery and defense against infection. In C. elegans, the UPRmt is activated during infection with the pathogen Pseudomonas aeruginosa-but only transiently. As this may reflect a pathogenic strategy to target a pathway required for host survival, we conducted a P. aeruginosa genetic screen to uncover mechanisms associated with this temporary activation. Here, we find that loss of the P. aeruginosa acyl-CoA dehydrogenase FadE2 prolongs UPRmt activity and extends host survival. FadE2 shows substrate preferences for the coenzyme A intermediates produced during the breakdown of the branched-chain amino acids valine and leucine. Our data suggests that during infection, FadE2 restricts the supply of these catabolites to the host hindering host energy metabolism in addition to the UPRmt. Thus, a metabolic pathway in P. aeruginosa contributes to pathogenesis during infection through manipulation of host energy status and mitochondrial stress signaling potential.
线粒体未折叠蛋白反应 (UPRmt) 是一种应激激活途径，可促进线粒体恢复和抵抗感染。在秀丽隐杆线虫中，UPRmt 在感染病原菌铜绿假单胞菌时被激活 - 但只是短暂的。由于这可能反映了一种针对宿主生存所需途径的致病策略，我们进行了铜绿假单胞菌的遗传筛选，以揭示与这种短暂激活相关的机制。在这里，我们发现铜绿假单胞菌酰基辅酶 A 脱氢酶 FadE2 的缺失延长了 UPRmt 的活性并延长了宿主的存活时间。FadE2 对在支链氨基酸缬氨酸和亮氨酸分解过程中产生的辅酶 A 中间体具有底物偏好性。我们的数据表明，在感染过程中，FadE2 限制了这些分解产物向宿主的供应，除了 UPRmt 之外，还会阻碍宿主的能量代谢。因此，铜绿假单胞菌中的代谢途径通过操纵宿主的能量状态和线粒体应激信号转导潜力来促进感染期间的发病机制。
