A role for SKN-1/Nrf in pathogen resistance and immunosenescence in Caenorhabditis elegans

• Published in: PLoS pathogens Vol. 8; no. 4; p. e1002673
• Main Authors: Papp, Diána, Csermely, Péter, Sőti, Csaba
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2012; Public Library of Science (PLoS)
• Subjects: Aging; Animals; Biology; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - immunology; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - immunology; DNA-Binding Proteins - immunology; Enterococcus; Enterococcus faecalis - immunology; Gene Expression Regulation; Genes; Health aspects; Immunity, Innate; Kinases; Nematodes; Oxidative Stress; p38 Mitogen-Activated Protein Kinases - metabolism; Physiological aspects; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa - immunology; RNA Interference; Signal Transduction; Stress; Transcription Factors - immunology; Virulence (Microbiology); United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1002673

A proper immune response ensures survival in a hostile environment and promotes longevity. Recent evidence indicates that innate immunity, beyond antimicrobial effectors, also relies on host-defensive mechanisms. The Caenorhabditis elegans transcription factor SKN-1 regulates xenobiotic and oxidative stress responses and contributes to longevity, however, its role in immune defense is unknown. Here we show that SKN-1 is required for C. elegans pathogen resistance against both Gram-negative Pseudomonas aeruginosa and Gram-positive Enterococcus faecalis bacteria. Exposure to P. aeruginosa leads to SKN-1 accumulation in intestinal nuclei and transcriptional activation of two SKN-1 target genes, gcs-1 and gst-4. Both the Toll/IL-1 Receptor domain protein TIR-1 and the p38 MAPK PMK-1 are required for SKN-1 activation by PA14 exposure. We demonstrate an early onset of immunosenescence with a concomitant age-dependent decline in SKN-1-dependent target gene activation, and a requirement of SKN-1 to enhance pathogen resistance in response to longevity-promoting interventions, such as reduced insulin/IGF-like signaling and preconditioning H(2)O(2) treatment. Finally, we find that wdr-23(RNAi)-mediated constitutive SKN-1 activation results in excessive transcription of target genes, confers oxidative stress tolerance, but impairs pathogen resistance. Our findings identify SKN-1 as a novel regulator of innate immunity, suggests its involvement in immunosenescence and provide an important crosstalk between pathogenic stress signaling and the xenobiotic/oxidative stress response.