title: Kinase suppressor of Ras-1 protects against pulmonary Pseudomonas aeruginosa infections.
abstract: Pseudomonas aeruginosa is a Gram-negative pathogen that causes severe infections in immunocompromised individuals and individuals with cystic fibrosis or chronic obstructive pulmonary disease (COPD). Here we show that kinase suppressor of Ras-1 (Ksr1)-deficient mice are highly susceptible to pulmonary P. aeruginosa infection accompanied by uncontrolled pulmonary cytokine release, sepsis and death, whereas wild-type mice clear the infection. Ksr1 recruits and assembles inducible nitric oxide (NO) synthase (iNOS) and heat shock protein-90 (Hsp90) to enhance iNOS activity and to release NO upon infection. Ksr1 deficiency prevents lung alveolar macrophages and neutrophils from activating iNOS, producing NO and killing bacteria. Restoring NO production restores the bactericidal capability of Ksr1-deficient lung alveolar macrophages and neutrophils and rescues Ksr1-deficient mice from P. aeruginosa infection. Our findings suggest that Ksr1 functions as a previously unknown scaffold that enhances iNOS activity and is therefore crucial for the pulmonary response to P. aeruginosa infections.
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Alexander
authors.initials: A
authors.lastname: Carpinteiro
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goettel
authors.forename: Matthias
authors.initials: M
authors.lastname: Soddemann
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D008171:Lung Diseases / Q000382:microbiology / Q000517:prevention & control*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology*; D011552:Pseudomonas Infections / Q000382:microbiology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D011494:Protein Kinases; C097199:KSR-1 protein kinase