Autophagy-Mediated Cholesterol Trafficking Controls Steroid Production

Texada, Michael J.; Malita, Alina; Christensen, Christian; Dall, Kathrine B.; Færgeman, Nils J.; Nagy, Stanislav; Halberg, Kenneth A.; Rewitz, Kim

doi:10.1016/j.devcel.2019.01.007

Cited by 56 publications

(63 citation statements)

References 63 publications

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“…In addition, the potential function of V‐ATPase in the autophagic process could regulate trafficking of cholesterol, a common precursor steroid, directly impacting ecdysone production. Indeed, loss of the autophagic pathway decreases ecdysone biosynthesis with a concomitant overgrowth of larvae 62 …”

Section: Discussionmentioning

confidence: 99%

The conserved microRNA miR‐8‐3p coordinates the expression of V‐ATPase subunits to regulate ecdysone biosynthesis forDrosophilametamorphosis

et al. 2020

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The steroid hormone ecdysone is the central regulator of insect metamorphosis, during which a growing, immature larva is remodeled, through pupal stages, to a reproductive adult. However, the underlying mechanisms of ecdysone-mediated metamorphosis remain to be fully elucidated. Here, we identified metamorphosis-associated microRNAs (miR-NAs) and their potential targets by cross-linking immunoprecipitation coupled with deep sequencing of endogenous Argonaute 1 protein in Drosophila. Interestingly, miR-8-3p targeted five Vha genes encoding distinct subunits of vacuolar H + -ATPase (V-ATPase), which has a vital role in the organellar acidification. The expression of ecdysone-responsive miR-8-3p is normally downregulated during Drosophila metamorphosis, but temporary overexpression of miR-8-3p in the whole body at the end of larval development led to defects in metamorphosis and survival, hallmarks of aberrant ecdysone signaling.In addition, miR-8-3p was expressed in the prothoracic gland (PG), which produces and releases ecdysone in response to prothoracicotropic hormone (PTTH). Notably, overexpression of miR-8-3p or knockdown of its Vha targets in the PG resulted in larger than normal, ecdysone-deficient larvae that failed to develop into the pupal stage but could be rescued by ecdysone feeding. Moreover, these animals showed defective PTTH signaling with a concomitant decrease in the expression of ecdysone biosynthetic genes. We also demonstrated that the regulatory network between the conserved miR-8-3p/miR-200 family and V-ATPase was functional in human cells. Consequently, our data indicate that the coordinated regulation of V-ATPase subunits by miR-8-3p is involved in Drosophila metamorphosis by controlling the ecdysone biosynthesis. K E Y W O R D S Ago1, CLIP-seq, ecdysone, metamorphosis, microRNA, V-ATPase 6450 | LIM et aL.

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Section: Discussionmentioning

confidence: 99%

The conserved microRNA miR‐8‐3p coordinates the expression of V‐ATPase subunits to regulate ecdysone biosynthesis forDrosophilametamorphosis

et al. 2020

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“…Warts (LATS1/2 in mammals) regulate steroid hormone production through an autophagydependent pathway (also called lipophagy). Precisely, Warts control the production of Drosophila steroid ecdysone through their effector microRNA bantam, which responds to nutrients, thus mobilizing the transport of the steroid precursor cholesterol 37 . Notably, YAP (mammalian Yki homolog) regulates steroidogenesis in tumor cells 38 , indicating that the regulation of steroidogenesis by the Wts-Yki pathway may be an evolutionarily conserved mechanism.…”

Section: Crosstalk Between the Hippo Pathway And Autophagy In Drosophilamentioning

confidence: 99%

Emerging role of the Hippo pathway in autophagy

Wang

Huang

et al. 2020

Cell Death Dis

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Autophagy is a dynamic circulatory system that occurs in all eukaryotic cells. Cytoplasmic material is transported to lysosomes for degradation and recovery through autophagy. This provides energy and macromolecular precursors for cell renewal and homeostasis. The Hippo-YAP pathway has significant biological properties in controlling organ size, tissue homeostasis, and regeneration. Recently, the Hippo-YAP axis has been extensively referred to as the pathophysiological processes regulating autophagy. Understanding the cellular and molecular basis of these processes is crucial for identifying disease pathogenesis and novel therapeutic targets. Here we review recent findings from Drosophila models to organisms. We particularly emphasize the regulation between Hippo core components and autophagy, which is involved in normal cellular regulation and the pathogenesis of human diseases, and its application to disease treatment.

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“…DR also induces autophagy and it is essential for extending lifespan [64]. At present, pathways related to autophagy are PI3K/Akt, EcR and mTOR [65,66]. In this study, many DEPs were not only found in the PI3K/Akt and mTOR pathways, but also involved in lysosomes according to the GO enrichments and KEGG pathway annotations, which provided clues for further research on the mechanism of DR induced autophagy.…”

Section: Autophagy Related Pathways Were Annotated During Drmentioning

confidence: 52%

Comparative proteomics analysis of dietary restriction in Drosophila

Gao

Zhu

et al. 2020

PLoS ONE

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To explore the underlying mechanism of dietary restriction (DR) induced lifespan extension in fruit flies at protein level, we performed proteome sequencing in Drosophila at day 7 (young) and day 42 (old) under DR and ad libitum (AL) conditions. A total of 18629 unique peptides were identified in Uniprot, corresponding to 3,662 proteins. Among them, 383 and 409 differentially expressed proteins (DEPs) were identified from comparison between DR vs AL at day 7 and 42, respectively. Bioinformatics analysis revealed that membrane-related processes, post-transcriptional processes, spliceosome and reproduction related processes, were highlighted significantly. In addition, expression of proteins involved in pathways such as spliceosomes, oxidative phosphorylation, lysosomes, ubiquitination, and riboflavin metabolism was relatively higher during DR. A relatively large number of DEPs were found to participate in longevity and age-related disease pathways. We identified 20 proteins that were consistently regulated during DR and some of which are known to be involved in ageing, such as mTORC1, antioxidant, DNA damage repair and autophagy. In the integration analysis, we found 15 genes that were stably regulated by DR at both transcriptional as well as translational levels. Our results provided a useful dataset for further investigations on the mechanism of DR and aging.

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Autophagy-Mediated Cholesterol Trafficking Controls Steroid Production

Cited by 56 publications

References 63 publications

The conserved microRNA miR‐8‐3p coordinates the expression of V‐ATPase subunits to regulate ecdysone biosynthesis forDrosophilametamorphosis

The conserved microRNA miR‐8‐3p coordinates the expression of V‐ATPase subunits to regulate ecdysone biosynthesis forDrosophilametamorphosis

Emerging role of the Hippo pathway in autophagy

Comparative proteomics analysis of dietary restriction in Drosophila

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