期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 11, 页码 7460-7469出版社
ELSEVIER
DOI: 10.1074/jbc.M113.518092
关键词
CFTR; Enzyme Catalysis; Gene Transcription; Mutagenesis Site Specific; Protein Conformation; X-ray Crystallography; Airway Infection; Epoxide Hydrolase; Substrate Specificity
资金
- National Institutes of Health [R01-AI091699]
- Training Grant Predoctoral Fellowships [T32-AI007519, T32-DK007301]
Background: Pathogens target airway clearance mechanisms to facilitate infection. Results: Sequence analysis reveals an Acinetobacter epoxide hydrolase (EH) that triggers loss of the cystic fibrosis transmembrane conductance regulator (CFTR). Conclusion: Homologous EH virulence factors found in a variety of opportunistic pathogens can impair CFTR, a key element of host airway defenses. Significance: EH virulence factors are potential therapeutic targets. Endocytic recycling of the cystic fibrosis transmembrane conductance regulator (CFTR) is blocked by the CFTR inhibitory factor (Cif). Originally discovered in Pseudomonas aeruginosa, Cif is a secreted epoxide hydrolase that is transcriptionally regulated by CifR, an epoxide-sensitive repressor. In this report, we investigate a homologous protein found in strains of the emerging nosocomial pathogens Acinetobacter nosocomialis and Acinetobacter baumannii (aCif). Like Cif, aCif is an epoxide hydrolase that carries an N-terminal secretion signal and can be purified from culture supernatants. When applied directly to polarized airway epithelial cells, mature aCif triggers a reduction in CFTR abundance at the apical membrane. Biochemical and crystallographic studies reveal a dimeric assembly with a stereochemically conserved active site, confirming our motif-based identification of candidate Cif-like pathogenic EH sequences. Furthermore, cif expression is transcriptionally repressed by a CifR homolog (aCifR) and is induced in the presence of epoxides. Overall, this Acinetobacter protein recapitulates the essential attributes of the Pseudomonas Cif system and thus may facilitate airway colonization in nosocomial lung infections.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据