Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection

Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22322-22330. doi: 10.1073/pnas.1909666116. Epub 2019 Oct 14.


Early host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from pathogen response genes while restoring somatic lipid distribution. In addition, activating p38/MAPK signaling in the absence of pathogens, is sufficient to drive SKN-1-dependent loss of somatic fat. These data define a SKN-1- and p38-dependent axis for coordinating pathogen responses, lipid homeostasis, and survival and identify transcriptional redirection, rather than inactivation, as a mechanism for counteracting the pleiotropic consequences of aberrant transcriptional activity.

Keywords: C. elegans; H3K4me3; SKN-1; lipid metabolism; pathogen.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epigenesis, Genetic*
  • Immunity, Innate
  • Lipid Metabolism*
  • MAP Kinase Signaling System
  • Oxidative Stress
  • Pseudomonas Infections / genetics*
  • Pseudomonas Infections / metabolism
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / pathogenicity
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Transcription Factors
  • skn-1 protein, C elegans
  • p38 Mitogen-Activated Protein Kinases