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1.
Mol Biol Rep ; 51(1): 657, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740636

RESUMEN

BACKGROUND: Mycobacterium tuberculosis (MTB) is the causative organism of tuberculosis. Cholesterol is a crucial carbon source required for the survival of MTB in host cells. Transcription factor NR1H3 along with its important target genes ABCA1 and ApoE play important role in removal of extra cholesterol from cells. Changes in the gene expression of NR1H3, ABCA1 and ApoE can affect cholesterol homeostasis and thus the survival of MTB in host cells.Therefore, the present study was designed to analyze the mRNA expression of NR1H3, ABCA1 and ApoE in pulmonary TB (PTB) patients from the population of Punjab, India. METHODS AND RESULTS: In this study, mRNA expression of the transcription factor NR1H3 and its target genes ABCA1 and ApoE was analyzed in 89 subjects, including 41 PTB patients and 48 healthy controls (HCs) by real-time quantitative PCR. It was found that the mRNA expression of both NR1H3 and ABCA1 genes was significantly lower in TB patients than in HCs (p < 0.001). Even after sex-wise stratification of the subjects, mRNA expression of NR1H3 and ABCA1 was found to be down-regulated in both male and female TB patients. No significant difference was observed in expression of ApoE (p = 0.98). CONCLUSIONS: The present study found that the mRNA expression of NR1H3 and ABCA1 is down-regulated in TB patients from Punjab state of India.


Asunto(s)
Transportador 1 de Casete de Unión a ATP , ARN Mensajero , Tuberculosis Pulmonar , Humanos , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Femenino , Masculino , India , Adulto , ARN Mensajero/genética , ARN Mensajero/metabolismo , Persona de Mediana Edad , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Mycobacterium tuberculosis/genética , Estudios de Casos y Controles , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo
2.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167207, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38701954

RESUMEN

PURPOSE: In this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism. METHODS: Exome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis. RESULTS: Our finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes. CONCLUSIONS: Our study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.


Asunto(s)
Sordera , Ictiosis , Linaje , Fosfolipasa C beta , Humanos , Sordera/genética , Sordera/patología , Fosfolipasa C beta/genética , Fosfolipasa C beta/metabolismo , Femenino , Masculino , Ictiosis/genética , Ictiosis/patología , Ictiosis/metabolismo , Heterocigoto , Ubiquitinación , Queratinocitos/metabolismo , Queratinocitos/patología , Secuenciación del Exoma , Adulto , Síndrome , Células HEK293 , Receptores de Esteroides
3.
Commun Biol ; 7(1): 521, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38702540

RESUMEN

Histone acetylation, a crucial epigenetic modification, is governed by histone acetyltransferases (HATs), that regulate many biological processes. Functions of HATs in insects are not well understood. We identified 27 HATs and determined their functions using RNA interference (RNAi) in the model insect, Tribolium castaneum. Among HATs studied, N-alpha-acetyltransferase 40 (NAA40) knockdown caused a severe phenotype of arrested larval development. The steroid hormone, ecdysone induced NAA40 expression through its receptor, EcR (ecdysone receptor). Interestingly, ecdysone-induced NAA40 regulates EcR expression. NAA40 acetylates histone H4 protein, associated with the promoters of ecdysone response genes: EcR, E74, E75, and HR3, and causes an increase in their expression. In the absence of ecdysone and NAA40, histone H4 methylation by arginine methyltransferase 1 (ART1) suppressed the above genes. However, elevated ecdysone levels at the end of the larval period induced NAA40, promoting histone H4 acetylation and increasing the expression of ecdysone response genes. NAA40 is also required for EcR, and steroid-receptor co-activator (SRC) mediated induction of E74, E75, and HR3. These findings highlight the key role of ecdysone-induced NAA40-mediated histone acetylation in the regulation of metamorphosis.


Asunto(s)
Ecdisona , Histona Acetiltransferasas , Histonas , Metamorfosis Biológica , Receptores de Esteroides , Tribolium , Animales , Tribolium/genética , Tribolium/crecimiento & desarrollo , Tribolium/metabolismo , Tribolium/enzimología , Histonas/metabolismo , Ecdisona/metabolismo , Acetilación , Metamorfosis Biológica/genética , Histona Acetiltransferasas/metabolismo , Histona Acetiltransferasas/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Larva/crecimiento & desarrollo , Larva/genética , Larva/metabolismo , Interferencia de ARN
4.
Cancer J ; 30(3): 142-152, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38753748

RESUMEN

ABSTRACT: Steroid receptors regulate gene expression for many important physiologic functions and pathologic processes. Receptors for estrogen, progesterone, and androgen have been extensively studied in breast cancer, and their expression provides prognostic information as well as targets for therapy. Noninvasive imaging utilizing positron emission tomography and radiolabeled ligands targeting these receptors can provide valuable insight into predicting treatment efficacy, staging whole-body disease burden, and identifying heterogeneity in receptor expression across different metastatic sites. This review provides an overview of steroid receptor imaging with a focus on breast cancer and radioligands for estrogen, progesterone, and androgen receptors.


Asunto(s)
Neoplasias de la Mama , Imagen Molecular , Tomografía de Emisión de Positrones , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico , Femenino , Imagen Molecular/métodos , Tomografía de Emisión de Positrones/métodos , Receptores de Esteroides/metabolismo , Receptores de Progesterona/metabolismo , Receptores de Estrógenos/metabolismo , Radiofármacos/metabolismo , Receptores Androgénicos/metabolismo
5.
Arch Insect Biochem Physiol ; 115(4): e22110, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38605666

RESUMEN

20-Hydroxyecdysone (20E) plays a vital role in a series of biological processes, via the nuclear receptors, EcR/USP by activating the ecdysone regulatory cascade. To clarify the role of EcR during the development of Grapholita molesta, the complementary DNA of ecdysone receptor isoform B1 (GmEcR-B1) was obtained from the transcriptome of G. molesta and verified by PCR. Alignment analysis revealed that the deduced protein sequence of GmEcR-B1 was highly homologous to EcR proteins identified in other lepidopteran species, especially the EcR-B1 isoform in Spodoptera litura. Quantitative real-time PCR showed that GmEcRs was expressed at all test developmental stages, and the expression level of GmEcRs was relatively higher during the period of the 3rd day of fifth instar larvae to 2nd of pupa than those in other stages. Moreover, the messenger RNA of GmEcRs was much more strongly expressed in the Malpighian tubule and epidermis than those in other tissues, which suggests that this gene may function in a tissue-specific manner during larval development. Silencing of GmEcRs could significantly downregulate the transcriptional level of ecdysone-inducible genes and result in increased mortality during metamorphosis and prolonged prepupal duration. Taken together, the present results indicate that GmEcRs may directly or indirectly affect the development of G. molesta.


Asunto(s)
Mariposas Nocturnas , Receptores de Esteroides , Animales , Mariposas Nocturnas/metabolismo , Ecdisona , Frutas/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Isoformas de Proteínas/genética
6.
Am J Surg Pathol ; 48(6): 681-690, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38682454

RESUMEN

Acinic cell carcinoma of the salivary gland (AciCC) is a low-grade carcinoma characterized by the overexpression of the transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3). AciCC has been the subject of a few molecular research projects. This study delves into AciCC's molecular landscape to identify additional alterations and explore their clinical implications. RNA sequencing and immunohistochemical staining for markers NR4A3/NR4A2, DOG-1, S100, and mammaglobin were utilized on 41 AciCCs and 11 secretory carcinoma (SC) samples. NR4A3 was evident in 35 AciCCs, while the residual 6 were NR4A3-negative and NR4A2-positive; SC samples were consistently NR4A3-negative. A novel fusion, PON3 exon 1- LCN1 exon 5, was detected in 9/41 (21.9%) AciCCs, exhibiting a classical histologic pattern with serous cell components growing in solid sheets alongside the intercalated duct-like component. Clinical follow-up of 39 patients over a median of 59 months revealed diverse prognostic outcomes: 34 patients exhibited no disease evidence, whereas the remaining 5 experienced poorer prognosis, involving local recurrence, lymph node, and distant metastasis, and disease-associated death, 4 of which harbored the PON3::LCN1 fusion. In addition, the HTN3::MSANTD3 fusion was recurrently identified in 7/41 AciCC cases. SC patients lacked both fusions. Immunohistochemistry uncovered differential expression of DOG-1, S100, and mammaglobin across samples, providing nuanced insights into their roles in AciCC. This study accentuates PON3::LCN1 and HTN3::MSANTD3 fusions as recurrent molecular events in AciCC, offering potential diagnostic and prognostic utility and propelling further research into targeted therapeutic strategies.


Asunto(s)
Biomarcadores de Tumor , Carcinoma de Células Acinares , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Neoplasias de las Glándulas Salivales , Humanos , Masculino , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Femenino , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/mortalidad , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/química , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Adulto , Anciano , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/análisis , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/análisis , Receptores de Hormona Tiroidea/metabolismo , Adulto Joven , Fusión Génica , Anciano de 80 o más Años , Proteínas de Unión al ADN/genética , Proteínas de Fusión Oncogénica/genética , Inmunohistoquímica
7.
Int J Mol Sci ; 25(8)2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38674140

RESUMEN

During choriogenesis in insects, chorion (eggshell) is formed by surrounding follicular epithelial cells in ovarioles. However, the regulatory endocrine factor(s) activating choriogenesis and the effect of chemical components on eggshell deserve further exploration. In two representative coleopterans, a coccinellid Henosepilachna vigintioctopunctata and a chrysomelid Leptinotarsa decemlineata, genes encoding the 20-hydroxyecdysone (20E) receptor heterodimer, ecdysone receptor (EcR) and ultraspiracle (USP), and two chitin biosynthesis enzymes UDP-N-acetylglucosamine pyrophosphorylase (UAP) and chitin synthase (ChS1), were highly expressed in ovaries of the young females. RNA interference (RNAi)-aided knockdown of either HvEcR or Hvusp in H. vigintioctopunctata inhibited oviposition, suppressed the expression of HvChS1, and lessened the positive signal of Calcofluor staining on the chorions, which suggests the reduction of a chitin-like substance (CLS) deposited on eggshells. Similarly, RNAi of LdEcR or Ldusp in L. decemlineata constrained oviposition, decreased the expression of LdUAP1 and LdChS1, and reduced CLS contents in the resultant ovaries. Knockdown of LdUAP1 or LdChS1 caused similar defective phenotypes, i.e., reduced oviposition and CLS contents in the L. decemlineata ovaries. These results, for the first time, indicate that 20E signaling activates choriogenesis in two coleopteran species. Moreover, our findings suggest the deposition of a CLS on the chorions.


Asunto(s)
Escarabajos , Ecdisona , Interferencia de ARN , Receptores de Esteroides , Transducción de Señal , Animales , Escarabajos/metabolismo , Escarabajos/genética , Femenino , Ecdisona/metabolismo , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Oviposición/efectos de los fármacos , Cáscara de Huevo/metabolismo , Ovario/metabolismo
8.
J Agric Food Chem ; 72(18): 10271-10281, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38655868

RESUMEN

Insect growth regulators (IGRs) are important green insecticides that disrupt normal growth and development in insects to reduce the harm caused by pests to crops. The ecdysone receptor (EcR) and three chitinases OfChtI, OfChtII, and OfChi-h are closely associated with the molting stage of insects. Thus, they are considered promising targets for the development of novel insecticides such as IGRs. Our previous work identified a dual-target compound 6j, which could act simultaneously on both EcR and OfChtI. In the present study, 6j was first found to have inhibitory activities against OfChtII and OfChi-h, too. Subsequently, taking 6j as a lead compound, 19 novel acetamido derivatives were rationally designed and synthesized by introducing an acetamido moiety into the amide bridge based on the flexibility of the binding cavities of 6j with EcR and three chitinases. Then, their insecticidal activities against Plutella xylostella (P. xylostella), Ostrinia furnacalis (O. furnacalis), and Spodoptera frugiperda (S. frugiperda) were carried out. The bioassay results revealed that most of these acetamido derivatives possessed moderate to good larvicidal activities against three lepidopteran pests. Especially, compound I-17 displayed excellent insecticidal activities against P. xylostella (LC50, 93.32 mg/L), O. furnacalis (LC50, 114.79 mg/L), and S. frugiperda (86.1% mortality at 500 mg/L), significantly better than that of 6j. In addition, further protein validation and molecular docking demonstrated that I-17 could act simultaneously on EcR (17.7% binding activity at 8 mg/L), OfChtI (69.2% inhibitory rate at 50 µM), OfChtII (71.5% inhibitory rate at 50 µM), and OfChi-h (73.9% inhibitory rate at 50 µM), indicating that I-17 is a potential lead candidate for novel multitarget IGRs. This work provides a promising starting point for the development of novel types of IGRs as pest management agents.


Asunto(s)
Quitinasas , Diseño de Fármacos , Proteínas de Insectos , Insecticidas , Hormonas Juveniles , Mariposas Nocturnas , Pirazoles , Spodoptera , Animales , Insecticidas/química , Insecticidas/farmacología , Insecticidas/síntesis química , Spodoptera/efectos de los fármacos , Spodoptera/crecimiento & desarrollo , Mariposas Nocturnas/efectos de los fármacos , Mariposas Nocturnas/crecimiento & desarrollo , Mariposas Nocturnas/metabolismo , Proteínas de Insectos/metabolismo , Proteínas de Insectos/química , Proteínas de Insectos/genética , Relación Estructura-Actividad , Hormonas Juveniles/farmacología , Hormonas Juveniles/química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Quitinasas/metabolismo , Quitinasas/química , Quitinasas/antagonistas & inhibidores , Receptores de Esteroides/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/química , Simulación del Acoplamiento Molecular , Larva/crecimiento & desarrollo , Larva/efectos de los fármacos , Acetamidas/farmacología , Acetamidas/química , Estructura Molecular
9.
Curr Biol ; 34(7): 1438-1452.e6, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38513654

RESUMEN

Steroid hormones regulate tissue development and physiology by modulating the transcription of a broad spectrum of genes. In insects, the principal steroid hormones, ecdysteroids, trigger the expression of thousands of genes through a cascade of transcription factors (TFs) to coordinate developmental transitions such as larval molting and metamorphosis. However, whether ecdysteroid signaling can bypass transcriptional hierarchies to exert its function in individual developmental processes is unclear. Here, we report that a single non-TF effector gene mediates the transcriptional output of ecdysteroid signaling in Drosophila myoblast fusion, a critical step in muscle development and differentiation. Specifically, we show that the 20-hydroxyecdysone (commonly referred to as "ecdysone") secreted from an extraembryonic tissue, amnioserosa, acts on embryonic muscle cells to directly activate the expression of antisocial (ants), which encodes an essential scaffold protein enriched at the fusogenic synapse. Not only is ants transcription directly regulated by the heterodimeric ecdysone receptor complex composed of ecdysone receptor (EcR) and ultraspiracle (USP) via ecdysone-response elements but also more strikingly, expression of ants alone is sufficient to rescue the myoblast fusion defect in ecdysone signaling-deficient mutants. We further show that EcR/USP and a muscle-specific TF Twist synergistically activate ants expression in vitro and in vivo. Taken together, our study provides the first example of a steroid hormone directly activating the expression of a single key non-TF effector gene to regulate a developmental process via inter-organ signaling and provides a new paradigm for understanding steroid hormone signaling in other developmental and physiological processes.


Asunto(s)
Proteínas de Drosophila , Receptores de Esteroides , Animales , Proteínas de Unión al ADN/metabolismo , Ecdisona , Ecdisteroides , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Muda/fisiología , Drosophila/fisiología , Regulación del Desarrollo de la Expresión Génica
10.
Mod Pathol ; 37(5): 100474, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38508521

RESUMEN

Recurrent gene fusions have been observed in epithelioid and myxoid variants of uterine leiomyosarcoma. PGR::NR4A3 fusions were recently described in a subset of epithelioid leiomyosarcomas exhibiting rhabdoid morphology. In this study, we sought to expand the clinical, morphologic, immunohistochemical, and genetic features of gynecologic leiomyosarcomas harboring NR4A3 rearrangements with PGR and novel fusion partners. We identified 9 gynecologic leiomyosarcomas harboring PGR::NR4A3, CARMN::NR4A3, ACTB::NR4A3, and possible SLCO5A1::NR4A3 fusions by targeted RNA sequencing. Tumors frequently affected premenopausal women, involving the uterine corpus, uterine cervix, or pelvis. All were similarly characterized by lobules of monomorphic epithelioid and/or spindled cells arranged in sheets, cords, trabeculae, and micro- and macrocysts associated with abundant myxoid matrix and hemorrhage, creating labyrinth-like or pulmonary edema-like architecture. Myogenic differentiation with frequent estrogen receptor and progesterone receptor staining and no CD10 expression characterized all tumors. All cases showed high NR4A3 RNA expression levels and NOR1 (NR4A3) nuclear staining similar to salivary gland acinic cell carcinomas and a subset of extraskeletal myxoid chondrosarcomas harboring NR4A3 rearrangements. NOR1 (NR4A3) immunohistochemistry may serve as a useful diagnostic marker of NR4A3 fusion-positive gynecologic leiomyosarcomas.


Asunto(s)
Leiomiosarcoma , Receptores de Hormona Tiroidea , Humanos , Femenino , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Persona de Mediana Edad , Adulto , Receptores de Hormona Tiroidea/genética , Receptores de Esteroides/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Proteínas de Unión al ADN/genética , Anciano , Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Femeninos/patología , Receptores de Progesterona/metabolismo , Receptores de Progesterona/genética , Proteínas de Fusión Oncogénica/genética , Fusión Génica
11.
Biochim Biophys Acta Biomembr ; 1866(4): 184308, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38437942

RESUMEN

Macroautophagy (hereafter autophagy) is an intracellular degradative pathway in budding yeast cells. Certain lipid types play essential roles in autophagy; yet the precise mechanisms regulating lipid composition during autophagy remain unknown. Here, we explored the role of the Osh family proteins in the modulating lipid composition during autophagy in budding yeast. Our results showed that osh1-osh7∆ deletions lead to autophagic dysfunction, with impaired GFP-Atg8 processing and the absence of autophagosomes and autophagic bodies in the cytosol and vacuole, respectively. Freeze-fracture electron microscopy (EM) revealed elevated phosphatidylinositol 4-phosphate (PtdIns(4)P) levels in cytoplasmic and luminal leaflets of autophagic bodies and vacuolar membranes in all deletion mutants. Phosphatidylserine (PtdSer) levels were significantly decreased in the autophagic bodies and vacuolar membranes in osh4∆ and osh5∆ mutants, whereas no significant changes were observed in other osh deletion mutants. Furthermore, we identified defects in autophagic processes in the osh4∆ and osh5∆ mutants, including rare autophagosome formation in the osh5∆ mutant and accumulation of autophagic bodies in the vacuole in the osh4∆ mutant, even in the absence of the proteinase inhibitor PMSF. These findings suggest that Osh4p and Osh5p play crucial roles in the transport of PtdSer to autophagic bodies and autophagosome membranes, respectively. The precise control of lipid composition in the membranes of autophagosomes and autophagic bodies by Osh4p and Osh5p represents an important regulatory mechanism in autophagy.


Asunto(s)
Autofagia , Fosfatos de Fosfatidilinositol , Fosfatidilserinas , Saccharomyces cerevisiae , Autofagosomas , Autofagia/genética , Fosfatidilserinas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Receptores de Esteroides , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
12.
Cell Rep ; 43(4): 113992, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38536815

RESUMEN

Insulin is packaged into secretory granules that depart the Golgi and undergo a maturation process that involves changes in the protein and lipid composition of the granules. Here, we show that insulin secretory granules form physical contacts with the endoplasmic reticulum and that the lipid exchange protein oxysterol-binding protein (OSBP) is recruited to these sites in a Ca2+-dependent manner. OSBP binding to insulin granules is positively regulated by phosphatidylinositol-4 (PI4)-kinases and negatively regulated by the PI4 phosphate (PI(4)P) phosphatase Sac2. Loss of Sac2 results in excess accumulation of cholesterol on insulin granules that is normalized when OSBP expression is reduced, and both acute inhibition and small interfering RNA (siRNA)-mediated knockdown of OSBP suppress glucose-stimulated insulin secretion without affecting insulin production or intracellular Ca2+ signaling. In conclusion, we show that lipid exchange at endoplasmic reticulum (ER)-granule contact sites is involved in the exocytic process and propose that these contacts act as reaction centers with multimodal functions during insulin granule maturation.


Asunto(s)
Colesterol , Retículo Endoplásmico , Secreción de Insulina , Insulina , Antígenos de Histocompatibilidad Menor , Receptores de Esteroides , Vesículas Secretoras , Retículo Endoplásmico/metabolismo , Vesículas Secretoras/metabolismo , Animales , Colesterol/metabolismo , Insulina/metabolismo , Receptores de Esteroides/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Ratones , Humanos , Calcio/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Glucosa/metabolismo
13.
Int J Mol Sci ; 25(5)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38474099

RESUMEN

Hypercapnia occurs when the partial pressure of carbon dioxide (CO2) in the blood exceeds 45 mmHg. Hypercapnia is associated with several lung pathologies and is transcriptionally linked to suppression of immune and inflammatory signalling through poorly understood mechanisms. Here we propose Orphan Nuclear Receptor Family 4A (NR4A) family members NR4A2 and NR4A3 as potential transcriptional regulators of the cellular response to hypercapnia in monocytes. Using a THP-1 monocyte model, we investigated the sensitivity of NR4A family members to CO2 and the impact of depleting NR4A2 and NR4A3 on the monocyte response to buffered hypercapnia (10% CO2) using RNA-sequencing. We observed that NR4A2 and NR4A3 are CO2-sensitive transcription factors and that depletion of NR4A2 and NR4A3 led to reduced CO2-sensitivity of mitochondrial and heat shock protein (Hsp)-related genes, respectively. Several CO2-sensitive genes were, however, refractory to depletion of NR4A2 and NR4A3, indicating that NR4As regulate certain elements of the cellular response to buffered hypercapnia but that other transcription factors also contribute. Bioinformatic analysis of conserved CO2-sensitive genes implicated several novel putative CO2-sensitive transcription factors, of which the ETS Proto-Oncogene 1 Transcription Factor (ETS-1) was validated to show increased nuclear expression in buffered hypercapnia. These data give significant insights into the understanding of immune responses in patients experiencing hypercapnia.


Asunto(s)
Receptores Nucleares Huérfanos , Receptores de Esteroides , Humanos , Receptores Nucleares Huérfanos/genética , Monocitos/metabolismo , Hipercapnia , Dióxido de Carbono , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Receptores de Esteroides/metabolismo , Proteínas de Unión al ADN , Receptores de Hormona Tiroidea
14.
Nat Commun ; 15(1): 1947, 2024 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-38431630

RESUMEN

Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions.


Asunto(s)
Endometriosis , Proteínas de Neoplasias , Receptores de Esteroides , Animales , Femenino , Humanos , Ratones , Endometriosis/genética , Endometriosis/metabolismo , Endometrio/metabolismo , Estrógenos/metabolismo , Proteínas de Neoplasias/metabolismo , Progesterona/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Esteroides/metabolismo
15.
J Cell Biol ; 223(6)2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38530252

RESUMEN

The integrity of the plasma membrane is critical to cell function and survival. Cells have developed multiple mechanisms to repair damaged plasma membranes. A key process during plasma membrane repair is to limit the size of the damage, which is facilitated by the presence of tetraspanin-enriched rings surrounding damage sites. Here, we identify phosphatidylserine-enriched rings surrounding damaged sites of the plasma membrane, resembling tetraspanin-enriched rings. Importantly, the formation of both the phosphatidylserine- and tetraspanin-enriched rings requires phosphatidylserine and its transfer proteins ORP5 and ORP9. Interestingly, ORP9, but not ORP5, is recruited to the damage sites, suggesting cells acquire phosphatidylserine from multiple sources upon plasma membrane damage. We further demonstrate that ORP9 contributes to efficient plasma membrane repair. Our results thus unveil a role for phosphatidylserine and its transfer proteins in facilitating the formation of tetraspanin-enriched macrodomains and plasma membrane repair.


Asunto(s)
Membrana Celular , Fosfatidilserinas , Tetraspaninas , Humanos , Células HeLa , Proteínas de la Membrana/metabolismo , Receptores de Esteroides/metabolismo
16.
PLoS Genet ; 20(3): e1011196, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38466721

RESUMEN

Hematophagous mosquitoes require vertebrate blood for their reproductive cycles, making them effective vectors for transmitting dangerous human diseases. Thus, high-intensity metabolism is needed to support reproductive events of female mosquitoes. However, the regulatory mechanism linking metabolism and reproduction in mosquitoes remains largely unclear. In this study, we found that the expression of estrogen-related receptor (ERR), a nuclear receptor, is activated by the direct binding of 20-hydroxyecdysone (20E) and ecdysone receptor (EcR) to the ecdysone response element (EcRE) in the ERR promoter region during the gonadotropic cycle of Aedes aegypti (named AaERR). RNA interference (RNAi) of AaERR in female mosquitoes led to delayed development of ovaries. mRNA abundance of genes encoding key enzymes involved in carbohydrate metabolism (CM)-glucose-6-phosphate isomerase (GPI) and pyruvate kinase (PYK)-was significantly decreased in AaERR knockdown mosquitoes, while the levels of metabolites, such as glycogen, glucose, and trehalose, were elevated. The expression of fatty acid synthase (FAS) was notably downregulated, and lipid accumulation was reduced in response to AaERR depletion. Dual luciferase reporter assays and electrophoretic mobility shift assays (EMSA) determined that AaERR directly activated the expression of metabolic genes, such as GPI, PYK, and FAS, by binding to the corresponding AaERR-responsive motif in the promoter region of these genes. Our results have revealed an important role of AaERR in the regulation of metabolism during mosquito reproduction and offer a novel target for mosquito control.


Asunto(s)
Aedes , Receptores de Esteroides , Animales , Femenino , Humanos , Aedes/genética , Aedes/metabolismo , Ecdisona/metabolismo , Mosquitos Vectores/genética , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Homeostasis/genética , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo
17.
J Med Chem ; 67(5): 3520-3541, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38417036

RESUMEN

Accumulating evidence has demonstrated a critical pathological role of oxysterol receptor GPR183 in various inflammatory and autoimmune diseases, including inflammatory bowel disease (IBD). However, the currently reported GPR183 antagonists are very limited and not qualified for in vivo studies due to their inferior druglike properties. Herein, we conducted a structural elaboration focusing on improving its PK and safety profile based on a reference antagonist NIBR189. Of note, compound 33, bearing an aminobenzothiazole motif, exhibited reduced hERG inhibition, improved PK properties, and robust antagonistic activity (IC50 = 0.82 nM) with high selectivity against GPR183. Moreover, compound 33 displayed strong in vitro antimigration and anti-inflammatory activity in monocytes. Oral administration of compound 33 effectively improved the pathological symptoms of DSS-induced experimental colitis. All of these findings demonstrate that compound 33 is a novel and promising GPR183 antagonist suitable for further investigation to treat IBD.


Asunto(s)
Colitis , Enfermedades Inflamatorias del Intestino , Oxiesteroles , Receptores de Esteroides , Humanos , Oxiesteroles/efectos adversos , Tiazoles/efectos adversos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Sulfato de Dextran , Receptores Acoplados a Proteínas G
18.
Proc Natl Acad Sci U S A ; 121(10): e2315493121, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38408242

RESUMEN

Oxysterol-binding protein-related proteins (ORPs) play key roles in the distribution of lipids in eukaryotic cells by exchanging sterol or phosphatidylserine for PI4P between the endoplasmic reticulum (ER) and other cell regions. However, it is unclear how their exchange capacity is coupled to PI4P metabolism. To address this question quantitatively, we analyze the activity of a representative ORP, Osh4p, in an ER/Golgi interface reconstituted with ER- and Golgi-mimetic membranes functionalized with PI4P phosphatase Sac1p and phosphatidylinositol (PI) 4-kinase, respectively. Using real-time assays, we demonstrate that upon adenosine triphosphate (ATP) addition, Osh4p creates a sterol gradient between these membranes, relying on the spatially distant synthesis and hydrolysis of PI4P, and quantify how much PI4P is needed for this process. Then, we develop a quantitatively accurate kinetic model, validated by our data, and extrapolate this to estimate to what extent PI4P metabolism can drive ORP-mediated sterol transfer in cells. Finally, we show that Sec14p can support PI4P metabolism and Osh4p activity by transferring PI between membranes. This study establishes that PI4P synthesis drives ORP-mediated lipid exchange and that ATP energy is needed to generate intermembrane lipid gradients. Furthermore, it defines to what extent ORPs can distribute lipids in the cell and reassesses the role of PI-transfer proteins in PI4P metabolism.


Asunto(s)
Fosfatos de Fosfatidilinositol , Receptores de Esteroides , Fosfatos de Fosfatidilinositol/metabolismo , Transporte Biológico , Esteroles/metabolismo , Fosfatidilserinas/metabolismo , Metabolismo de los Lípidos , Adenosina Trifosfato/metabolismo , Membrana Celular/metabolismo , Receptores de Esteroides/metabolismo
19.
Biochem Pharmacol ; 222: 116063, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38373593

RESUMEN

Steroid hormones play an important role in physiological processes. The classical pathway of steroid actions is mediated by nuclear receptors, which regulate genes to modify biological processes. Non-genomic pathways of steroid actions are also known, mediated by cell membrane-located seven transmembrane domain receptors. Sex steroids and glucocorticoids have several membrane receptors already identified to mediate their rapid actions. However, mineralocorticoids have no identified membrane receptors, although their rapid actions are also measurable. In non-vascular smooth muscles (bronchial, uterine, gastrointestinal, and urinary), the rapid actions of steroids are mediated through the modification of the intracellular Ca2+ level by various Ca-channels and the cAMP and IP3 system. The non-genomic action can be converted into a genomic one, suggesting that these distinct pathways may interconnect, resulting in convergence between them. Sex steroids mostly relax all the non-vascular smooth muscles, except androgens and progesterone, which contract colonic and urinary bladder smooth muscles, respectively. Corticosteroids also induce relaxation in bronchial and uterine tissues, but their actions on gastrointestinal and urinary bladder smooth muscles have not been investigated yet. Bile acids also contribute to the smooth muscle contractility. Although the therapeutic application of the rapid effects of steroid hormones and their analogues for smooth muscle contractility disorders seems remote, the actions and mechanism discovered so far are promising. Further research is needed to expand our knowledge in this field by using existing experience. One of the greatest challenges is to separate genomic and non-genomic effects, but model molecules are available to start this line of research.


Asunto(s)
Receptores de Esteroides , Esteroides , Esteroides/farmacología , Esteroides/fisiología , Hormonas Esteroides Gonadales/farmacología , Hormonas Esteroides Gonadales/metabolismo , Progesterona/farmacología , Progesterona/metabolismo , Glucocorticoides , Músculo Liso/metabolismo , Receptores de Esteroides/metabolismo
20.
Dev Biol ; 508: 8-23, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38199580

RESUMEN

Steroid hormones play various physiological roles including metabolism and reproduction. Steroid hormones in insects are ecdysteroids, and the major form in Drosophila melanogaster is ecdysone. In Drosophila males, the accessory gland is responsive to nutrient-dependent regulation of fertility/fecundity. The accessory gland is composed of two types of binucleated epithelial cells: a main cell and a secondary cell (SC). The transcription factors Defective proventriculus (Dve), Abdominal-B, and Ecdysone receptors (EcRs) are strongly expressed in adult SCs. We show that this EcR expression is regulated by parallel pathways of nutrient signaling and the Dve activity. Induction of Dve expression is also dependent on nutrient signaling, and it becomes nutrient signal-independent during a restricted period of development. Forced dve expression during the restricted period significantly increased the number of SCs. Here, we provide evidence that the level of nutrient signal-dependent Dve expression during the restricted period determines the number of SCs, and that ecdysone signaling is also crucial to optimize male fecundity through nutrient signal-dependent survival and maturation of SCs.


Asunto(s)
Proteínas de Drosophila , Receptores de Esteroides , Animales , Masculino , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Ecdisona/metabolismo , Fertilidad , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Esteroides/metabolismo
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