The Toll Signaling Pathway Targets the Insulin-like Peptide Dilp6 to Inhibit Growth in Drosophila

Suzawa, Miyuki; Muhammad, Nigel M.; Joseph, Bradley S.; Bland, Michelle L.

doi:10.1016/j.celrep.2019.07.015

Cited by 49 publications

(47 citation statements)

References 53 publications

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“…4), leading to progressive loss of energy stores and consequently, higher mortality [138]. Later, a more direct link between IIS and immunity was established through the demonstration that activation of Toll signalling in the fat bodygenetically or by infection with Micrococcus luteusinhibits IIS activity [139], targeting specifically DILP6 [140], which is mainly produced in the fat body [134][135][136], and resulting in decreased triglyceride storage and larval growth. Furthermore, Toll signalling interferes with IIS activation through inhibition of Akt by PDK1 [141].…”

Section: Insulin-like Peptidesmentioning

confidence: 99%

Endocrine regulation of immunity in insects

2020

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In insects as seen in vertebrates, distinct hormones control the immune response either positively or negatively depending on physiological circumstances. Conversely, the immune system also impacts endocrine regulation. This interplay is itself determined by the environmental cues and organismal homeostatic control. This review surveys different aspects of these intricate relationships with emphasis on the endocrine regulation of immunity in insects, its mechanisms and implications on metabolic adaptation and behaviour.

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Section: Insulin-like Peptidesmentioning

confidence: 99%

Endocrine regulation of immunity in insects

2020

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“…AMPs are secreted by fat body cells via the classical ER-Golgi-secretory vesicle pathway (Shandala et al, 2011). Acute activation of Toll signaling leads to three-fold or greater induction of 17 of the 37 AMPs encoded in the Drosophila genome (Suzawa et al, 2019). We reasoned that ER expansion and phospholipid synthesis may serve the process of AMP production and secretion.…”

Section: Amp Synthesis Contributes To Induction Of Kennedy Pathway Enmentioning

confidence: 99%

“…Lipid storage defects can be elicited by genetic activation of the Toll and Imd pathways, indicating that metabolic changes are dictated not only by pathogen interaction but also by signaling from the host immune system. Expression of a constitutively-active Toll receptor, Toll 10b , in larval fat body inhibits whole-animal growth, disrupts insulin signaling in fat body, and reduces triglyceride storage (DiAngelo et al, 2009;Roth et al, 2018;Suzawa et al, 2019). Similarly, activation of the Imd pathway in larval fat body results in decreased triglyceride levels and impaired whole-animal growth (Davoodi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

Martínez

Bland

2020

Preprint

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During infection, cellular resources are allocated toward synthesis and secretion of effector proteins that neutralize and kill invading pathogens. In Drosophila, antimicrobial peptides (AMPs) are produced in the fat body, an organ that also serves as a major nutrient storage depot.Here we asked how the innate immune response activated by fat body Toll signaling alters lipid metabolism as a model for understanding how the cellular and energetic demands of the immune response are met. We find that genetic activation of fat body Toll signaling leads to a tissueautonomous reduction in triglyceride storage that is paralleled by decreased transcript levels of Lipin and midway, enzymes that carry out the final steps of triglyceride synthesis. In contrast, Kennedy pathway enzymes that synthesize phospholipids and their products, phosphatidylcholine and phosphatidylethanolamine, are induced in fat bodies with active Toll signaling. Induction of these enzymes depends on the unfolded protein response mediator Xbp1, and examination of endoplasmic reticulum (ER) morphology by transmission electron microscopy revealed significantly expanded ER in fat body cells with active Toll signaling.Together these results indicate that Toll signaling induces a metabolic switch from triglyceride storage to phospholipid synthesis and ER expansion; this occurs in response to AMP production and may sustain AMP synthesis and secretion during infection. Better understanding of how this anabolic switch in lipid metabolism is induced, as well as the long-term consequences of reduced triglyceride storage at the expense of phospholipid synthesis, should yield insight into metabolic diseases that stem from chronic inflammation.

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“…The function of the fat body as a major immune-responsive tissue has also been characterized (LEMAITRE AND HOFFMANN 2007). In response to infection, the fat body activates nuclear factor-B (NF-B) signaling to produce and secrete antimicrobial peptides (AMPs) into the hemolymph (LEMAITRE AND HOFFMANN 2007;BUCHON et al 2014;ROTH et al 2018;SUZAWA et al 2019). There is also evidence that the fat body acts as a detoxification tissue based on the expression of members of the Cytochrome P450 (Cyp450) superfamily of monooxygenases, which are enzymes involved in metabolizing foreign substances and drugs (FEYEREISEN 1999;CHUNG et al 2009) and implicated in resistance to insecticides (TERHZAZ et al 2015).…”

Section: Introductionmentioning

confidence: 99%

The Nuclear Receptor Seven Up Regulates Genes Involved in Immunity and Xenobiotic Response in the AdultDrosophilaFemale Fat Body

Weaver¹,

Drummond‐Barbosa²

2020

G3 Genes|Genomes|Genetics

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The physiology of organisms depends on inter-organ communication in response to changes in the environment. Nuclear receptors are broadly expressed transcription factors that respond to circulating molecules to control many biological processes, including immunity, detoxification, and reproduction. Although the tissue-intrinsic roles of nuclear receptors in reproduction have been extensively studied, there is increasing evidence that nuclear receptor signaling in peripheral tissues can also influence oogenesis. We previously showed that the Drosophila nuclear receptor Seven up (Svp) is required in the adult fat body to regulate distinct steps of oogenesis; however, the relevant downstream targets of Svp remain unknown. Here, we took an RNA sequencing approach to identify candidate Svp targets specifically in the adult female fat body that might mediate this response. svp knockdown in the adult female fat body significantly downregulated immune genes involved in the first line of pathogen defense, suggesting a role for Svp in stimulating early immunity. In addition, we found that Svp transcriptionally regulates genes involved in each step of the xenobiotic detoxification response. Based on these findings, we propose a testable model in which Svp functions in the adult female fat body to stimulate early defense against pathogens and facilitate detoxification as part of its mechanisms to promote oogenesis.

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The Toll Signaling Pathway Targets the Insulin-like Peptide Dilp6 to Inhibit Growth in Drosophila

Cited by 49 publications

References 53 publications

Endocrine regulation of immunity in insects

Endocrine regulation of immunity in insects

Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

The Nuclear Receptor Seven Up Regulates Genes Involved in Immunity and Xenobiotic Response in the AdultDrosophilaFemale Fat Body

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