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Insect hormone prothoracicotropic hormone (PTTH) regulates lifespan through temporal and spatial activation of NF-κB signaling during Drosophila metamorphosis [2]

ABSTRACT: The prothoracicotropic hormone (PTTH) is a well-known neuropeptide that regulates insect metamorphosis (the juvenile-to-adult transition) by inducing the biosynthesis of steroid hormones, similar to the hypothalamic-pituitary-gonadal control of mammalian puberty. However, the role of Ptth in adult physiology and longevity is largely unexplored. Here, we show that Ptth loss-of-function mutants are long-lived and exhibit increased resistance to oxidative stress in Drosophila. Intriguingly, we find that loss of Ptth blunt age-dependent upregulation of NF-κB signaling specifically in fly oenocytes, the homolog of mammalian hepatocytes. We further show that oenocyte-specific overexpression of NF-κB/Relish blocks the lifespan extension of Ptth mutants, suggesting that Ptth regulates lifespan through oenocyte-specific NF-κB signaling. Surprisingly, adult-specific knockdown of Ptth did not prolong lifespan, indicating that Ptth might control longevity through developmental programs. Our developmental transcriptomic analysis reveals an interesting activation of NF-κB signaling during fly metamorphosis, which is attenuated in Ptth mutants. Intriguingly, the knockdown of NF-κB/Relish, specifically in oenocytes during metamorphosis, significantly prolongs the lifespan of adult flies. Thus, our findings uncover an unexpected role of insect hormone PTTH in controlling adult lifespan through temporal and spatial activation of NF-κB signaling in developing hepatocytes.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE271166 | GEO | 2025/04/22

REPOSITORIES: GEO

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Project description:The intricate regulation of gut homeostasis is dependent on a fine-tuned regulation of the host defense to avoid detrimental immune activation. We have previously applied Drosophila to show that mutants of the short isoform of the POU transcription factor Pdm1/nubbin (nub) have a constitutively active immune response, altered gut microbiota and shortened lifespan. Here, we studied the role of Nub-PB, the larger isoform derived from the nub gene. Both Nub protein isoforms contain the C-terminal POU and Homeo domains whereas Nub-PB encompasses a longer N-terminal end. Microarray analysis revealed that targeted misexpression of Nub-PB in immunocompetent organs triggers a strong and broad expression of immune genes in a comparable manner to Nub-PD mutants. The seemingly antagonistic functions of the two isoforms were confirmed by co-overexpression of both forms, which resulted in normal expression levels of antimicrobial peptide (AMP) genes. Cell line experiments demonstrated a synergistic activation of AMPs by the combined transfection with Nub-PB and NF-kB/Relish. In agreement with this finding, Relish was indispensable for Nub-PB-driven diptericin expression, suggesting that Nub-PB acts as a Relish co-activator. Moreover, Nub-PB triggered strong expression of gut-specific drosomycin-like genes in a JAK/STAT pathway-dependent manner. Using RNA interference, we found that Nub-PB influences antimicrobial peptide expression in gut but not fat body tissues. Moreover, Nub-PB expression levels in gut enterocytes correlated with the gut bacterial load as well as host lifespan, suggesting a profound role in host immunity. Surprisingly, Nub-PB-overexpression caused a hypersensitive infection phenotype as flies succumbed within 24 h to orally administered Erwinia carotovora carotovora 15. Nub-PB thus appears to be a central activator of gut immunity that requires tight control, executed at least in part, by isoform antagonism to maintain immune homeostasis.

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Insect hormone prothoracicotropic hormone (PTTH) regulates lifespan through temporal and spatial activation of NF-κB signaling during Drosophila metamorphosis [2]

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