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Regulation of germline proteostasis by insulin/IGF-1 signaling

ABSTRACT: Regulation of germline proteostasis by insulin/IGF-1 signaling

PROVIDER: PRJNA1078387 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28019319_1.fastq.gz	Fastqsanger.gz
	SRR28019319_2.fastq.gz	Fastqsanger.gz
	SRR28019320_1.fastq.gz	Fastqsanger.gz
	SRR28019320_2.fastq.gz	Fastqsanger.gz
	SRR28019321_1.fastq.gz	Fastqsanger.gz

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Regulation of germline proteostasis by insulin/IGF-1 signaling

Project description:Gametogenesis involves active protein synthesis and heavily relies on proteostasis. How animals regulate germline proteostasis at the organismal level is poorly understood. Our recent work in C. elegans indicates that germline development requires coordinated activities between insulin/IGF-1 signaling and HSF-1, the transcriptional activator of many molecular chaperones in stress and physiological conditions. In this study, we show that HSF-1 is important for germline proteostasis at ambient temperature. Depletion of HSF-1 from germ cells impairs chaperone gene expression, causing protein degradation and aggregation and, consequently, declines in fecundity and gamete quality. Reduced insulin/IGF-1 signaling confers germ cells' tolerance to limited protein folding capacity and proteotoxic stress by lowering ribosome biogenesis and translation. Interestingly, regulation of germline proteostasis by insulin/IGF-1 signaling occurs non-cell-autonomously. Our data suggest that insulin/IGF-1 signaling controls the expression of the evolutionarily conserved intestinal peptide transporter PEPT-1 via its downstream transcription factor FOXO/DAF-16, therefore allowing dietary proteins to be incorporated into an amino acid pool that fuels ribosomal biogenesis and translation in the germline. We propose that this pathway plays a critical role in regulating germline protein synthesis, which must be at balance with HSF-1-dependent protein folding to achieve proteostasis in gametogenesis.

2024-05-20 | GSE256186 | GEO

Viral Insulin/IGF-like Peptides Inhibit IGF-1 Receptor Signaling to Enhance Viral Replication

Project description:The insulin/IGF system plays a central role in regulating metabolism and growth. We identified viral insulin/IGF1-like peptides (VILPs) in Iridoviridae and investigated their role in host-virus interactions. Using Grouper Iridovirus (GIV) on grouper and zebrafish cells, we show that VILPs are early viral genes and are secreted during infection. VILPs activate insulin receptor (IR) and IGF-1 receptor (IGF1R) phosphorylation and stimulate the PI3K pathway. Supernatants from infected cells trigger dose and time-dependent signaling with GIV-VILP selectively interacts with IGF1R. Functionally, IR inhibition suppresses GIV replication, whereas IGF1R inhibition enhances it, and IGF-1 stimulation reduces replication. During infection, GIV-VILP competes with IGF-1, attenuating IGF1R signaling and reducing proliferation. Transcriptome analysis confirms negative regulation of cell cycle pathways. Using a zebrafish infection model, we demonstrate VILP expression and IGF-1 signaling inhibition. Our findings reveal a viral mimicry mechanism that modulates host IGF-1 signaling to promote viral replication.

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Loss of the proteostasis modulator AIRAPL causes myeloid transformation by deregulating IGF-1 signaling

Project description:Transcriptional profiling of human acute myeloid leukemia cells lines HEL and SET2 transduced with an IGF1R shRNA and miR-125a sponge. AIRAPL (arsenite-inducible regulatory particle-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but whose biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/IGF-1 signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as in mice carrying the JAK2-V617F mutation, which demonstrates the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and unveil novel therapeutic targets for these frequent hematological neoplasias.

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Project description:Insulin and insulin-like growth factors (IGF-1 and IGF-2) regulate metabolism, growth, and development via related receptors. In contexts such as brain function or fetal development, coordinated signaling by all three hormones is essential. We report the engineering of [GluB10, D-HisB24, GlyB31, TyrB32]-insulin (1Ins), an analog with high affinity for IR-A, IR-B, and especially IGF-1R. 1Ins binds IGF-1R ~1,000-fold more strongly than native insulin, approaching IGF-1 levels. CryoEM structures reveal how minimal substitutions in 1Ins enable effective binding to both IR-A and IGF-1R. In neuronal cells, 1Ins robustly activates both IR and IGF-1R pathways, promotes survival, and exceeds native ligands in neuroprotective assays. In vivo, 1Ins regulates glucose effectively in mice and rats. Phosphoproteomic profiling confirms dual pathway activation and identifies targets unique to 1Ins. These findings demonstrate that rational design of dual-receptor agonists can yield potent, versatile ligands with therapeutic promise in metabolic control, neuroprotection, and regeneration.

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FOXO and HSF1 rejuvenate immunity via positive feedback regulation of insulin/IGF-1 signaling

Project description:A hallmark of aging is immunosenescence, a decline in immune function that appeared to be inevitable. Surprisingly, here we show that genetic inhibition of DAF-2/insulin/IGF-1 receptor drastically delays immunosenescence and even rejuvenates immunity in C. elegans. We find that p38 mitogen activated protein kinase (PMK-1), a key determinant of immunosenescence in wild-type, is dispensable for this rejuvenated immunity. Instead, we demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of zip-10/bZip transcription factor, which in turn down-regulates ins-7, an agonistic insulin-like peptide, for further reduction in insulin/IGF-1 signaling (IIS). Thus, reduced IIS bypasses immunosenescence and rejuvenates immunity via up-regulating anti-aging transcription factors that regulate an endocrine insulin-like peptide through a positive feedback mechanism. Because many functions of IIS are conserved across phyla, our study may lead to developing strategies for immune rejuvenation in humans.

2021-02-26 | GSE137861 | GEO

Starvation-induced changes in somatic Insulin/IGF-1R signaling drive metabolic programming across generations

Project description:Exposure to adverse nutritional and metabolic environments during critical periods of development can exert long-lasting effects on health outcomes of an individual and its descendants. Although such metabolic programming has been observed in multiple species and in response to distinct nutritional stressors, conclusive insights into signaling pathways and mechanisms responsible for initiating, mediating and manifesting changes to metabolism and behavior across generations remain scarce. By employing a multigenerational starvation paradigm in C. elegans, we show that starvation-induced changes in DAF-16/FoxO activity, the main downstream target of insulin/IGF-1 receptor signaling, are responsible for metabolic programming phenotypes. Tissue-specific depletion of DAF-16/FoxO during distinct developmental time points further demonstrates that DAF-16/FoxO acts in somatic tissues, but not directly in the germline, to both initiate and manifest metabolic programming. In conclusion, our study deciphers multifaceted and critical roles of highly conserved insulin/IGF-1 receptor signaling in determining health outcomes and behavior across generations.

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Viral Insulin/IGF-like Peptides Inhibit IGF-1 Receptor Signaling to Enhance Viral Replication

Project description:Viral Insulin/IGF-like Peptides Inhibit IGF-1 Receptor Signaling to Enhance Viral Replication

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Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling-induced dietary peptide uptake via PEPT-1.

Project description: Not available

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The Insulin/IGF Signaling Cascade Modulates SUMOylation to Regulate Aging and Proteostasis in C. elegans.

Project description:In this project we asked how reducing the activity of the insulin/IGF signaling (IIS) cascade by knocking down the expression of daf-2, affects global protein SUMOylation of C. elegans. We found that among other proteins, IIS reduction lowers the SUMOylation of CAR-1, a protein that negatively regulates the activity of the worm’s notch receptor, GLP-1. Thus, the knockdown of car-1 hyper-activates GLP-1, shortens lifespan and exposes the worm to toxic protein aggregation (proteotoxicity). In contrast, the expression of a SUMOylation resistant CAR-1 (K185R) promotes longevity and protects model nematodes from proteotoxicity.

2018-06-06 | PXD010011 | Pride

Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling-induced dietary peptide uptake via PEPT-1

Project description: Not available

| S-SCDT-10_1038-S44318-024-00234-X | biostudies-other