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C. elegans SWAN-1 Binds to EGL-9 and Regulates HIF-1- Mediated Resistance to the Bacterial Pathogen Pseudomonas aeruginosa PAO1
PLoS Pathogens
  • Zhiyong Shao, Iowa State University
  • Yi Zhang, Iowa State University
  • Qi Ye, Iowa State University
  • Jenifer N. Saldhana, Iowa State University
  • Jo Anne Powell-Coffman, Iowa State University
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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-offunction 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.

This article is from PLoS Pathogens 6 (2010): e1001075, doi:10.1371/journal.ppat.1001075. Posted with permission.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Zhiyong Shao et al
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Zhiyong Shao, Yi Zhang, Qi Ye, Jenifer N. Saldhana, et al.. "C. elegans SWAN-1 Binds to EGL-9 and Regulates HIF-1- Mediated Resistance to the Bacterial Pathogen Pseudomonas aeruginosa PAO1" PLoS Pathogens Vol. 6 Iss. 8 (2010) p. 1 - 11
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