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Pseudomonas aeruginosa  is a nearly ubiquitous human pathogen, and infections can be lethal to patients with impaired respiratory and immune systems. Prior studies have established that strong loss-of-function mutations in the  egl-9  gene protect the nematode  C. elegans  from  P. aeruginosa  PAO1 fast killing. EGL-9 inhibits the HIF-1 transcription factor via two pathways. First, EGL-9 is the enzyme that targets HIF-1 for oxygen-dependent degradation via the VHL-1 E3 ligase. Second, EGL-9 inhibits HIF-1-mediated gene expression through a VHL-1-independent mechanism. Here, we show that a loss-of-function mutation in  hif-1  suppresses  P. aeruginosa  PAO1 resistance in  egl-9  mutants. Importantly, we find stabilization of HIF-1 protein is not sufficient to protect  C. elegans  from  P. aeruginosa  PAO1 fast killing. However, mutations that inhibit both EGL-9 pathways result in higher levels of HIF-1 activity and confer resistance to the pathogen. Using forward genetic screens, we identify additional mutations that confer resistance to  P. aeruginosa . In genetic backgrounds that stabilize  C. elegans  HIF-1 protein, loss-of-function mutations in  swan-1  increase the expression of hypoxia response genes and protect  C. elegans  from  P. aeruginosa  fast killing. SWAN-1 is an evolutionarily conserved WD-repeat protein belonging to the AN11 family. Yeast two-hybrid and co-immunoprecipitation assays show that EGL-9 forms a complex with SWAN-1. Additionally, we present genetic evidence that the DYRK kinase MBK-1 acts downstream of SWAN-1 to promote HIF-1-mediated transcription and to increase resistance to  P. aeruginosa . These data support a model in which SWAN-1, MBK-1 and EGL-9 regulate HIF-1 transcriptional activity and modulate resistance to  P. aeruginosa  PAO1 fast killing.

C. elegans SWAN-1 Binds to EGL-9 and Regulates HIF-1-Mediated Resistance to the Bacterial Pathogen Pseudomonas aeruginosa PAO1