CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection
CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection
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DOI：
10.1126/scitranslmed.aav4634
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发表时间：
2019-07-03
影响因子：
17.1
通讯作者：
Prince, Alice
中科院分区：
文献类型：
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作者：
Riquelme, Sebastian A.;Lozano, Carmen;Prince, Alice
10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）是一种肿瘤抑制因子，以调节细胞增殖和代谢而闻名。PTEN与囊性纤维化（CF）跨膜传导调节因子（CFTR）在质膜处形成复合物，并且已知该复合物在CF中功能受损。在这里，我们证明了PTEN和CFTR功能障碍的联合作用刺激线粒体活性，导致琥珀酸和活性氧的过度释放。这种环境促进了铜绿假单胞菌（优先代谢琥珀酸的细菌）在气道中的定植，并刺激了由免疫应答基因1（IRG 1）和衣康酸盐主导的抗炎宿主反应。由这些菌株诱导的骨髓细胞的募集在清除感染方面是无效的，并且在CFTR-PTEN轴功能障碍下积累的吞噬细胞的数量增加。由于PTEN活性受损导致的线粒体功能的这种中心代谢缺陷导致CF中的铜绿假单胞菌感染。
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor best known for regulating cell proliferation and metabolism. PTEN forms a complex with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the plasma membrane, and this complex is known to be functionally impaired in CF. Here, we demonstrated that the combined effect of PTEN and CFTR dysfunction stimulates mitochondrial activity, resulting in excessive release of succinate and reactive oxygen species. This environment promoted the colonization of the airway by Pseudomonas aeruginosa, bacteria that preferentially metabolize succinate, and stimulated an anti-inflammatory host response dominated by immune-responsive gene 1 (IRG1) and itaconate. The recruitment of myeloid cells induced by these strains was inefficient in clearing the infection and increased numbers of phagocytes accumulated under CFTR-PTEN axis dysfunction. This central metabolic defect in mitochondrial function due to impaired PTEN activity contributes to P. aeruginosa infection in CF.