Auxin-Inducible Degron System Reveals Temporal-Spatial Roles of HSF-1 and Its Transcriptional Program in Lifespan Assurance

Morphis, Allison; Edwards, Stacey L.; Erdenebat, Purevsuren; Kumar, Lalit; Li, Jian

doi:10.3389/fragi.2022.899744

Cited by 3 publications

(1 citation statement)

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“…HSF-1 is well-known for its roles in proteotoxic stress responses, such as against heat shock, but it also regulates gene expression in physiological conditions during development, reproduction, and aging ( 9, 22, 23 ). In a previous study, we identified the HSF-1 transcriptional program in C. elegans germline by combining tissue-specific HSF-1 depletion using the auxin-inducible degron (AID) system with ChIP-seq and RNA-seq analyses at ambient temperature ( 9 ).…”

Section: Resultsmentioning

confidence: 99%

Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling via the intestinal peptide transporter PEPT-1

Muhammad,

Edwards,

Morphis

et al. 2024

Preprint

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Gametogenesis involves active protein synthesis and heavily relies on proteostasis. How animals regulate germline proteostasis at the organismal level is poorly understood. TakingC. elegansas a model, we show that germline proteostasis requires coupled activities of HSF-1-dependent protein folding and insulin/IGF-1 signaling controlled protein synthesis. 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’ resilience to limited protein folding capacity and proteotoxic stress by lowering ribosome biogenesis and the rate of translation. Interestingly, insulin/IGF-1 signaling promotes 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 protein synthesis in the germline. We propose that this non-cell-autonomous pathway plays a critical role in regulating proteostasis in gametogenesis.TeaserInsulin/IGF-1 signaling regulates proteostasis in gametogenesis via the control of dietary protein absorption.

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Section: Resultsmentioning

confidence: 99%

Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling via the intestinal peptide transporter PEPT-1

Muhammad,

Edwards,

Morphis

et al. 2024

Preprint

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Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process

Salminen

2022

Cell. Mol. Life Sci.

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The antagonistic pleiotropy hypothesis is a well-known evolutionary theory to explain the aging process. It proposes that while a particular gene may possess beneficial effects during development, it can exert deleterious properties in the aging process. The aryl hydrocarbon receptor (AhR) has a significant role during embryogenesis, but later in life, it promotes several age-related degenerative processes. For instance, AhR factor (i) controls the pluripotency of stem cells and the stemness of cancer stem cells, (ii) it enhances the differentiation of embryonal stem cells, especially AhR signaling modulates the differentiation of hematopoietic stem cells and progenitor cells, (iii) it also stimulates the differentiation of immunosuppressive Tregs, Bregs, and M2 macrophages, and finally, (iv) AhR signaling participates in the differentiation of many peripheral tissues. On the other hand, AhR signaling is involved in many processes promoting cellular senescence and pathological processes, e.g., osteoporosis, vascular dysfunction, and the age-related remodeling of the immune system. Moreover, it inhibits autophagy and aggravates extracellular matrix degeneration. AhR signaling also stimulates oxidative stress, promotes excessive sphingolipid synthesis, and disturbs energy metabolism by catabolizing NAD+ degradation. The antagonistic pleiotropy of AhR signaling is based on the complex and diverse connections with major signaling pathways in a context-dependent manner. The major regulatory steps include, (i) a specific ligand-dependent activation, (ii) modulation of both genetic and non-genetic responses, (iii) a competition and crosstalk with several transcription factors, such as ARNT, HIF-1α, E2F1, and NF-κB, and (iv) the epigenetic regulation of target genes with binding partners. Thus, not only mTOR signaling but also the AhR factor demonstrates antagonistic pleiotropy in the regulation of the aging process.

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Engineering the auxin-inducible degron system for tunablein vivocontrol of organismal physiology

Vicencio,

Chihara,

Eder

et al. 2024

Preprint

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The physiological mechanisms governing health and disease exhibit complex interactions between multiple genes and gene products. To study the dynamics of living systems, researchers need experimental methods capable of producing calibrated, quantitative perturbationsin vivo— perturbations that cannot be obtained using classical genetics, RNAi interference, or small molecule drugs. Recently, an auxin-inducible degron (AID) system has been developed to allow targeted degradation of proteins using small-molecule activators, providing spatiotemporal control of protein abundance. However, a better understanding of the biochemical activities of AID system components in their physiological context is needed to design quantitative interventions.Here, we apply engineering approaches to characterize and understand the performance of several AID technologies and then improve this performance in the multicellular animalCaenorhabditis elegans. We 1) develop new technologies that allow for a careful calibration of AID activity for specific purposes; 2) develop new TIR1 enzyme constructs with improved performance over existing constructs; 3) develop an approach to simultaneously and independently degrade target proteins in distinct tissues; and finally, 4) develop an approach for pan-organismal protein degradation by re-engineering the TIR1 enzyme. Taken together, these advances enable new quantitative experimental approaches to study the cellular and systems dynamics of animals.

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Auxin-Inducible Degron System Reveals Temporal-Spatial Roles of HSF-1 and Its Transcriptional Program in Lifespan Assurance

Cited by 3 publications

References 53 publications

Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling via the intestinal peptide transporter PEPT-1

Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling via the intestinal peptide transporter PEPT-1

Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process

Engineering the auxin-inducible degron system for tunablein vivocontrol of organismal physiology

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