Figure 7. Working model for HIF-1-mediated inflammatory regulation.

A. Proposed model of noncanonical HIF-1 inhibition lifting HIF-1-mediated repression of host defense genes. Infection by S. aureus causes induction of host defense genes. Some of these genes are also induced by HIF, while others are repressed by HIF. Genes induced by HIF include genes that mediate resistance to pore-forming toxins (PFT) and P. aeruginosa. Genes that are repressed by HIF include genes that mediate resistance to S. aureus. Canonical HIF regulation mediated by VHL-1 requires EGL-9 catalytic activity and controls the gene-inductive activity of HIF. O₂ is a signal driving HIF inhibition by the canonical pathway. Noncanonical HIF regulation, which is independent of EGL-9 catalytic activity but requires SWAN-1, controls the gene-repressive activity of HIF. The signal(s) that regulate noncanonical signaling are currently not known. B. Diagram of predicted and observed phenotypes in mutants defective in canonical or noncanonical HIF signaling.