Abstract
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 H2O2 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.
Highlights
A proper immune response ensures survival in a hostile environment and contributes to longevity
To study the role of SKN-1 in C. elegans immunity, we examined the pathogen resistance of animals in the absence of SKN-1. skn1(zu135) allele is considered to be a genetic null mutation as it creates a premature stop codon that affects all SKN-1 isoforms [15]. skn-1(zu135) mutant worms were first exposed to the Gramnegative Pseudomonas aeruginosa (PA14) strain
We focused on further defining the role of SKN-1 in the antibacterial response against P. aeruginosa
Summary
A proper immune response ensures survival in a hostile environment and contributes to longevity. The nematode Caenorhabditis elegans provides a valuable genetic tool for studying innate immunity and various aspects of host-pathogen interactions. During infection, both bacterial virulence factors and host antimicrobial defense mechanisms present oxidative and proteotoxic noxae inducing tissue-damage, especially in the intestine [1,2,3,4,5]. Several self-protective stress-response regulators including the forkhead transcription factor DAF-16/FOXO [6], the heat shock transcription factor HSF-1 [7] and the X-box binding protein 1 (XBP-1) [8] are required for robust immunity. The DAF-16-regulated antioxidant enzymes SOD-3 and CTL-2 contribute to immunity by protecting intestinal cells from reactive oxygen species during exposure to Enterococcus faecalis [9]. Hyper-activation of DAF-16 enhances susceptibility to bacterial infection [10]
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