A Membrane Transporter Is Required for Steroid Hormone Uptake in Drosophila

Okamoto, Naoki; Viswanatha, Raghuvir; Bittar, Riyan; Li, Zhongchi; Haga-Yamanaka, Sachiko; Perrimon, Norbert; Yamanaka, Naoaki

doi:10.1016/j.devcel.2018.09.012

Cited by 109 publications

(140 citation statements)

References 77 publications

(96 reference statements)

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“…Notably, however, a recent study challenges the dogma of freely membrane-permeable steroids (and maybe also other smaller compounds). Okamoto et al (154) have reported that in Drosophila, steroid hormones require a protein transporter for passing through cellular membranes. Moreover, once steroids become sulfated, they are trapped within the cell (5).…”

Section: Jbc Reviews: Green and Red Sulfation Pathwaysmentioning

confidence: 99%

Sulfation pathways from red to green

Günal

Hardman

Kopriva

et al. 2019

Journal of Biological Chemistry

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Edited by Joseph M. JezSulfur is present in the amino acids cysteine and methionine and in a large range of essential coenzymes and cofactors and is therefore essential for all organisms. It is also a constituent of sulfate esters in proteins, carbohydrates, and numerous cellular metabolites. The sulfation and desulfation reactions modifying a variety of different substrates are commonly known as sulfation pathways. Although relatively little is known about the function of most sulfated metabolites, the synthesis of activated sulfate used in sulfation pathways is essential in both animal and plant kingdoms. In humans, mutations in the genes encoding the sulfation pathway enzymes underlie a number of developmental aberrations, and in flies and worms, their loss-of-function is fatal. In plants, a lower capacity for synthesizing activated sulfate for sulfation reactions results in dwarfism, and a complete loss of activated sulfate synthesis is also lethal. Here, we review the similarities and differences in sulfation pathways and associated processes in animals and plants, and we point out how they diverge from bacteria and yeast. We highlight the open questions concerning localization, regulation, and importance of sulfation pathways in both kingdoms and the ways in which findings from these "red" and "green" experimental systems may help reciprocally address questions specific to each of the systems.Sulfur (S) is an essential nutrient for all life forms. It is present in a plethora of metabolites of primary and secondary metabolism, most prominently in the amino acids cysteine and methionine, and cofactors such as iron-sulfur clusters, lipoic acid, and CoA. In the majority of these metabolites, sulfur is present in its reduced form of organic thiols; however, some compounds contain S in its oxidized form of sulfate (1, 2). Sulfate is transferred to suitable substrates onto hydroxyl or amino groups by sulfotransferases (3,4). These biological sulfation reactions as well as desulfation catalyzed by sulfatases are often denoted as sulfation pathways (Fig. 1) (5, 6).The activated sulfate for the sulfation pathways, 3Ј-phosphoadenosine 5-phosphosulfate (PAPS), 3 is formed from sulfate by two ATP-dependent steps: adenylation, i.e. the transfer of the AMP moiety of ATP to sulfate to form adenosine 5Ј-phosphosulfate (APS) by ATP sulfurylase (ATPS), and the phosphorylation of APS at its 3Ј-OH group by APS kinase. The two enzymes are either fused into a single enzyme PAPS synthase (PAPSS) in the animal kingdom or occur as independent proteins in the green lineage (7). The by-product of PAPS-dependent sulfation reactions, 3Ј-phosphoadenosine 5-phosphate (PAP), is finally dephosphorylated to AMP by 3Ј-nucleotidases. This reaction to remove PAP is important beyond the sulfation pathways, as PAP accumulation has many additional physiological effects (8,9). Sulfate activation to APS or PAPS is a prerequisite not only for sulfation pathways but also for primary sulfate assimilation in plants, algae, bacteria, and fungi (2). Parti...

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Section: Jbc Reviews: Green and Red Sulfation Pathwaysmentioning

confidence: 99%

Sulfation pathways from red to green

Günal

Hardman

Kopriva

et al. 2019

Journal of Biological Chemistry

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“…A second paper combined results from a pooled CRISPR screen in the Perrimon lab with a more traditional in vivo approach from Naoki Yamanaka's lab at the University of California Riverside. Both groups had converged on a gene that mediates reception of a molting hormone called ecdysone 5 , but the in vivo approach involved creating and then assaying numerous RNAi-mutated flies. The CRISPR screen found the hit in an unbiased fashion and with fewer false positives to sort through and validate, says Viswanatha.…”

Section: Into the Poolmentioning

confidence: 99%

CRISPR takes genetic screens forward

Neff¹

2019

Lab Anim

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“…The classical model of diffusion-mediated steroid transport is not sufficient to explain the steroid trafficking within and across cells, and therefore specific receptormediated transport and signalling mechanisms are gaining in importance 25,26 . To date, the data regarding P5 inter-and intra-cellular transport is very limited.…”

Section: Click-proteomics Reveals P5 Interactions With Cellular Transmentioning

confidence: 99%

CLICK-enabled analogues reveal pregnenolone interactomes in cancer and immune cells

Roy

Sipthorp²,

Mahata

et al. 2019

Preprint

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Pregnenolone (P5) promotes prostate cancer cell growth, and de novo synthesis of intratumoural P5 is a potential cause of development of castration-resistance. Immune cells can also synthesize P5 de novo. Despite its biological importance, little is known about P5's mode of actions, which appears to be context-dependent and pleiotropic. A comprehensive proteome-wide spectrum of P5-binding proteins that are involved in its trafficking and functionality remains unknown. Here, we describe an approach that integrates chemical biology for probe synthesis with chemoproteomics to map P5protein interactions in live prostate cancer cells and murine CD8 + T cells. We subsequently identified P5-binding proteins potentially involved in P5-trafficking, and in P5's non-genomic action that may drive the promotion of castrate-resistance prostate cancer and regulate CD8 + T cell function. We envisage that this methodology could be employed for other steroids to map their interactomes directly in a broad range of living cells, tissues and organisms.glioma it restricts tumour growth 11 . The mode-of-action of P5 in tumours is incompletely understood. In the nervous system, P5 is known to regulate synapse formation, outgrowth of neurites and enhances myelinization 12 , improves cognitive and memory function 13 .During immune response against helminth parasite infection T helper cells synthesize P5 to restore immune homeostasis 4 . Up to now, we do not have a proteome-wide description of the P5-interacting molecules in any living cells.Traditionally, steroid hormones have been considered to act by regulating transcription 14 . However, rapid activity of steroid hormones can be mediated by nongenomic pathways 15 . Non-genomic pathways appear to mediate P5 activity 16 in a cell type-specific and context-dependent manner, indicating a need for proteome-wide studies to map the full spectrum of P5 functions.Here, we have developed a chemical biology method to generate clickable P5analogues for use in living cells. Exploiting these P5-probes in combination with quantitative mass-spectrometry, we profiled global P5-protein interactions directly in two distinct cell types: a steroid-sensitive cell line derived from a metastatic prostate cancer patient (i.e. LNCaP) and de novo P5-producing mouse CD8 + T cells.Altogether, we identified 62 high-confidence P5 binding and about 387 potential P5binding proteins localized in the nucleus, mitochondria and endoplasmic reticulum.These proteins include receptors, channels, transporters, cytoskeletal proteins such as vimentin and enzymes, of which many represent novel interactions. Overall, we identified P5-binding proteins potentially involved in inter-and intra-cellular P5trafficking and P5's non-genomic action that drives prostate cancer promotion of castration-resistance, and mediates CD8 + T cell regulation.

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A Membrane Transporter Is Required for Steroid Hormone Uptake in Drosophila

Cited by 109 publications

References 77 publications

Sulfation pathways from red to green

Sulfation pathways from red to green

CRISPR takes genetic screens forward

CLICK-enabled analogues reveal pregnenolone interactomes in cancer and immune cells

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