RESUMO
Endocrine signaling networks control diverse biological processes and life history traits across metazoans. In both invertebrate and vertebrate taxa, steroid hormones regulate immune system function in response to intrinsic and environmental stimuli, such as microbial infection. The mechanisms of this endocrine-immune regulation are complex and constitute an ongoing research endeavor facilitated by genetically tractable animal models. The 20-hydroxyecdysone (20E) is the major steroid hormone in arthropods, primarily studied for its essential role in mediating developmental transitions and metamorphosis; 20E also modulates innate immunity in a variety of insect taxa. This review provides an overview of our current understanding of 20E-mediated innate immune responses. The prevalence of correlations between 20E-driven developmental transitions and innate immune activation are summarized across a range of holometabolous insects. Subsequent discussion focuses on studies conducted using the extensive genetic resources available in Drosophila that have begun to reveal the mechanisms underlying 20E regulation of immunity in the contexts of both development and bacterial infection. Lastly, I propose directions for future research into 20E regulation of immunity that will advance our knowledge of how interactive endocrine networks coordinate animals' physiological responses to environmental microbes.
Assuntos
Drosophila melanogaster , Regulação da Expressão Gênica no Desenvolvimento , Animais , Drosophila melanogaster/genética , Esteroides , Drosophila/genética , Imunidade Inata/genética , Hormônios Juvenis , Ecdisterona , Metamorfose Biológica/genéticaRESUMO
Perturbations to animal-associated microbial communities (the microbiota) have deleterious effects on various aspects of host fitness, but the molecular processes underlying these impacts are poorly understood. Here, we identify a connection between the microbiota and the neuronal factor Arc1 that affects growth and metabolism in Drosophila. We find that Arc1 exhibits tissue-specific microbiota-dependent expression changes, and that germ-free flies bearing a null mutation of Arc1 exhibit delayed and stunted larval growth, along with a variety of molecular, cellular and organismal traits indicative of metabolic dysregulation. Remarkably, we show that the majority of these phenotypes can be fully suppressed by mono-association with a single Acetobacter sp. isolate, through mechanisms involving both bacterial diet modification and live bacteria. Additionally, we provide evidence that Arc1 function in key neuroendocrine cells of the larval brain modulates growth and metabolic homeostasis under germ-free conditions. Our results reveal a role for Arc1 in modulating physiological responses to the microbial environment, and highlight how host-microbe interactions can profoundly impact the phenotypic consequences of genetic mutations in an animal host.
Assuntos
Proteínas do Citoesqueleto/metabolismo , Drosophila/metabolismo , Drosophila/fisiologia , Microbiota/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Acetobacter/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Homeostase/fisiologia , Larva/metabolismo , Larva/fisiologia , Mutação/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , FenótipoRESUMO
The maintenance of cellular proteins in a biologically active and structurally stable state is a vital endeavor involving multiple cellular pathways. One such pathway is the ubiquitin-proteasome system that represents a major route for protein degradation, and reductions in this pathway usually have adverse effects on the health of cells and tissues. Here, we demonstrate that loss-of-function mutants of the Caenorhabditis elegans proteasome subunit, RPN-10, exhibit moderate proteasome dysfunction and unexpectedly develop both increased longevity and enhanced resistance to multiple threats to the proteome, including heat, oxidative stress, and the presence of aggregation prone proteins. The rpn-10 mutant animals survive through the activation of compensatory mechanisms regulated by the conserved SKN-1/Nrf2 and ELT-2/GATA transcription factors that mediate the increased expression of genes encoding proteasome subunits as well as those mediating oxidative- and heat-stress responses. Additionally, we find that the rpn-10 mutant also shows enhanced activity of the autophagy-lysosome pathway as evidenced by increased expression of the multiple autophagy genes including atg-16.2, lgg-1, and bec-1, and also by an increase in GFP::LGG-1 puncta. Consistent with a critical role for this pathway, the enhanced resistance of the rpn-10 mutant to aggregation prone proteins depends on autophagy genes atg-13, atg-16.2, and prmt-1. Furthermore, the rpn-10 mutant is particularly sensitive to the inhibition of lysosome activity via either RNAi or chemical means. We also find that the rpn-10 mutant shows a reduction in the numbers of intestinal lysosomes, and that the elt-2 gene also plays a novel and vital role in controlling the production of functional lysosomes by the intestine. Overall, these experiments suggest that moderate proteasome dysfunction could be leveraged to improve protein homeostasis and organismal health and longevity, and that the rpn-10 mutant provides a unique platform to explore these possibilities.
Assuntos
Adaptação Fisiológica , Autofagia , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição GATA/metabolismo , Lisossomos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Fatores de Transcrição/metabolismo , Animais , Núcleo Celular/metabolismo , Sobrevivência Celular , Sequência Conservada , Sistema Digestório/metabolismo , Regulação da Expressão Gênica , Resposta ao Choque Térmico/genética , Mutação/genética , Estresse Oxidativo , Dobramento de Proteína , Subunidades Proteicas/metabolismo , Análise de Sequência de RNA , Estresse Fisiológico , Ubiquitina/metabolismoRESUMO
The molecular mechanisms that distinguish immunosenescence from general age-related decline are poorly understood. We addressed this by exposing Day 1 and Day 5 adults of Caenorhabditis elegans to Pseudomonas aeruginosa strain PA01, an opportunistic pathogen. Day 5 adult C. elegans exhibited greater vulnerability to infection as compared to Day 1 C. elegans. Using TMT6-plex isobaric labeling and reductive dimethylation, we identified 55 proteins whose levels were altered following infection of Day 1 and Day 5 adults. Proteins whose levels changed in response to infection at both ages were strongly enriched for locomotory functions underscoring the importance of pathogen avoidance mechanisms. In Day 1 C. elegans, proteins with reproductive functions were highly enriched, whereas, Day 5 worms showed elevated levels of factors representing stress response pathways such as unfolded protein response (UPR) and metabolic functions. We also found that PA01 infection is associated with elevated protein carbonylation, an irreversible marker for oxidative stress. We explored the function of UNC-60, a cytoskeletal protein whose levels were changed by both age and infection, and found that mutants of unc-60 have reduced lifespan. Overall, our data provide novel insights into the relationship between age and immunosenescence in metazoans. SIGNIFICANCE: There are gaps in our knowledge pertaining to how aging influences an organism's response to pathogen exposure. In C. elegans, pathogen exposure to P. aeruginosa PA01 results in shortened lifespan, which is more pronounced in Day 5, compared to Day 1 adult worms. The proteome has age-specific responses to this exposure, and notably affects development, reproduction, metabolism, protein folding/unfolding, locomotion, and response to stress. This study addresses the molecular links between aging and immunosenescence in invertebrates.