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Updated: Jan 5, 2026
Immunometabolic Circuits in Infection for Advancing Host Directed Therapies
Published on: September 13, 2024
Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection
James D Nhan1,2, Christian D Turner1,2, Sarah M Anderson3
1Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089.
Abstract:
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.
Insights
The transcription factor SKN-1 coordinates pathogen defense and lipid metabolism in C. elegans. Transcriptional redirection of SKN-1 activity mitigates negative health outcomes during infection and stress.
Area of Science:
- * Molecular biology
- * Genetics
- * Immunology
Background:
- * Early host responses are crucial for combating infections.
- * The transcription factor SKN-1 regulates defense mechanisms against toxins and bacteria in *C. elegans*.
- * Constitutive SKN-1 activation leads to detrimental lipid redistribution and reduced lifespan.
Purpose of the Study:
- * To investigate the role of SKN-1 in coordinating host defense and lipid homeostasis during *Pseudomonas aeruginosa* infection.
- * To explore mechanisms by which SKN-1 activity is regulated to prevent adverse metabolic consequences.
- * To identify signaling pathways that influence SKN-1-mediated responses.
Main Methods:
- * Exposure of *C. elegans* to *Pseudomonas aeruginosa* and oxidative stress.
- * Modulation of the epigenetic landscape to influence SKN-1 activity.
- * Genetic activation of p38/MAPK signaling.
- * Measurement of somatic and germline lipid stores.
- * Analysis of SKN-1 target gene expression.
Main Results:
- * *Pseudomonas aeruginosa* infection rapidly depletes somatic lipid stores in *C. elegans*.
- * Modulating epigenetics redirects SKN-1 activity, alleviating negative metabolic effects.
- * Oxidative stress also redirects SKN-1 away from pathogen genes, restoring lipid distribution.
- * p38/MAPK signaling activation can induce SKN-1-dependent fat loss even without infection.
Conclusions:
- * A SKN-1 and p38/MAPK signaling axis coordinates pathogen response, lipid homeostasis, and survival.
- * Transcriptional redirection, not inactivation, is a key mechanism to manage SKN-1's pleiotropic effects.
- * Understanding this axis offers insights into host defense and metabolic regulation.
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