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1.
bioRxiv ; 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39386652

RESUMO

Pyruvate occupies a central node in carbohydrate metabolism such that how it is produced and consumed can optimize a cell for energy production or biosynthetic capacity. This has been primarily studied in proliferating cells, but observations from the post-mitotic Drosophila fat body led us to hypothesize that pyruvate fate might dictate the rapid cell growth observed in this organ during development. Indeed, we demonstrate that augmented mitochondrial pyruvate import prevented cell growth in fat body cells in vivo as well as in cultured mammalian hepatocytes and human hepatocyte-derived cells in vitro. This effect on cell size was caused by an increase in the NADH/NAD+ ratio, which rewired metabolism toward gluconeogenesis and suppressed the biomass-supporting glycolytic pathway. Amino acid synthesis was decreased, and the resulting loss of protein synthesis prevented cell growth. Surprisingly, this all occurred in the face of activated pro-growth signaling pathways, including mTORC1, Myc, and PI3K/Akt. These observations highlight the evolutionarily conserved role of pyruvate metabolism in setting the balance between energy extraction and biomass production in specialized post-mitotic cells.

2.
Cell Rep ; 43(9): 114693, 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39235946

RESUMO

Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Enterócitos , Fator 4 Nuclear de Hepatócito , Metabolismo dos Lipídeos , Animais , Fator 4 Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Enterócitos/metabolismo , Drosophila melanogaster/metabolismo , Mucosa Intestinal/metabolismo , Intestinos
3.
Genetics ; 228(2)2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39196789

RESUMO

Hybrid male sterility is one of the fastest evolving intrinsic reproductive barriers between recently isolated populations. A leading explanation for the evolution of hybrid male sterility involves genomic conflicts with meiotic drivers in the male germline. There are, however, few examples directly linking meiotic drive to hybrid sterility. In this study, we report that the Sex-Ratio chromosome of Drosophila pseudoobscura, which causes X-chromosome drive within the USA subspecies, causes near-complete male sterility when it is moved into the genetic background of the Bogota subspecies. In addition, we show that this new form of sterility is genetically distinct from the sterility of F1 hybrid males in crosses between USA males and Bogota females. Our observations provide a tractable study system where noncryptic drive within species is transformed into strong hybrid sterility between very young subspecies.


Assuntos
Drosophila , Hibridização Genética , Infertilidade Masculina , Meiose , Animais , Drosophila/genética , Drosophila/fisiologia , Meiose/genética , Masculino , Feminino , Infertilidade Masculina/genética , Cromossomo X/genética , Razão de Masculinidade
4.
bioRxiv ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38798315

RESUMO

Hybrid male sterility is one of the fastest evolving intrinsic reproductive barriers between recently isolated populations. A leading explanation for the evolution of hybrid male sterility involves genomic conflicts with meiotic drivers in the male germline. There are, however, few examples directly linking meiotic drive to hybrid sterility. Here, we report that the Sex-Ratio chromosome of Drosophila pseudoobscura, which causes X-chromosome drive within the USA subspecies, causes near complete male sterility when moved into the genetic background of the Bogota subspecies. In addition, we show that this new form of sterility is genetically distinct from the sterility of F1 hybrid males in crosses between USA males and Bogota females. Our observations provide a tractable study system where non-cryptic drive within species is transformed into strong hybrid sterility between very young subspecies.

5.
Dev Biol ; 481: 104-115, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34648816

RESUMO

Pulses of the steroid hormone ecdysone act through transcriptional cascades to direct the major developmental transitions during the Drosophila life cycle. These include the prepupal ecdysone pulse, which occurs 10 â€‹hours after pupariation and triggers the onset of adult morphogenesis and larval tissue destruction. E93 encodes a transcription factor that is specifically induced by the prepupal pulse of ecdysone, supporting a model proposed by earlier work that it specifies the onset of adult development. Although a number of studies have addressed these functions for E93, little is known about its roles in the salivary gland where the E93 locus was originally identified. Here we show that E93 is required for development through late pupal stages, with mutants displaying defects in adult differentiation and no detectable effect on the destruction of larval salivary glands. RNA-seq analysis demonstrates that E93 regulates genes involved in development and morphogenesis in the salivary glands, but has little effect on cell death gene expression. We also show that E93 is required to direct the proper timing of ecdysone-regulated gene expression in salivary glands, and that it suppresses earlier transcriptional programs that occur during larval and prepupal stages. These studies support the model that the stage-specific induction of E93 in late prepupae provides a critical signal that defines the end of larval development and the onset of adult differentiation.


Assuntos
Proteínas de Drosophila/metabolismo , Ecdisona/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Metamorfose Biológica/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Ecdisona/metabolismo , Larva , Fatores de Transcrição/genética
6.
Dev Biol ; 479: 51-60, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34331899

RESUMO

Successful reproduction is dependent on the transfer of male seminal proteins to females upon mating. These proteins arise from secretory tissues in the male reproductive tract, including the prostate and seminal vesicles in mammals and the accessory gland in insects. Although detailed functional studies have provided important insights into the mechanisms by which accessory gland proteins support reproduction, much less is known about the molecular mechanisms that regulate their expression within this tissue. Here we show that the Drosophila HR39 nuclear receptor is required for the proper expression of most genes that encode male accessory gland proteins. Consistent with this role, HR39 mutant males are infertile. In addition, tissue-specific RNAi and genetic rescue experiments indicate that HR39 acts within the accessory glands to regulate gene expression and male fertility. These results provide new directions for characterizing the mammalian orthologs of HR39, the SF-1 and LRH-1 nuclear receptors, both of which are required for glandular secretions and reproduction. In addition, our studies provide a molecular mechanism to explain how the accessory glands can maintain the abundant levels of seminal fluid production required to support fertility.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Infertilidade Masculina/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Fertilidade/genética , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Genitália Masculina/metabolismo , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Próstata/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Reprodução/genética
7.
Dev Dyn ; 250(5): 640-651, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33368768

RESUMO

BACKGROUND: Lipid levels are maintained by balancing lipid uptake, synthesis, and mobilization. Although many studies have focused on the control of lipid synthesis and mobilization, less is known about the regulation of lipid digestion and uptake. RESULTS: Here we show that the Drosophila E78A nuclear receptor plays a central role in intestinal lipid homeostasis through regulation of the CG17192 digestive lipase. E78A mutant adults fail to maintain proper systemic lipid levels following eclosion, with this effect largely restricted to the intestine. Transcriptional profiling by RNA-seq revealed a candidate gene for mediating this effect, encoding the predicted adult intestinal lipase CG17192. Intestine-specific disruption of CG17192 results in reduced lipid levels similar to that seen in E78A mutants. In addition, dietary supplementation with free fatty acids, or intestine-specific expression of either E78A or CG17192, is sufficient to restore lipid levels in E78A mutant adults. CONCLUSION: These studies support the model that E78A is a central regulator of adult lipid homeostasis through its effects on CG17192 expression and lipid digestion. This work also provides new insights into the control of intestinal lipid uptake and demonstrate that nuclear receptors can play an important role in these pathways.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Metabolismo dos Lipídeos , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Sequência de Bases , Gorduras na Dieta , Drosophila/genética , Proteínas de Drosophila/genética , Feminino , Regulação da Expressão Gênica , Homeostase , Intestinos/enzimologia , Lipase/metabolismo , Masculino , Receptores Citoplasmáticos e Nucleares/genética
8.
Dev Cell ; 48(2): 200-214.e6, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30554999

RESUMO

Animals must adjust their metabolism as they progress through development in order to meet the needs of each stage in the life cycle. Here, we show that the dHNF4 nuclear receptor acts at the onset of Drosophila adulthood to direct an essential switch in lipid metabolism. Lipid stores are consumed shortly after metamorphosis but contribute little to energy metabolism. Rather, dHNF4 directs their conversion to very long chain fatty acids and hydrocarbons, which waterproof the animal to preserve fluid homeostasis. Similarly, HNF4α is required in mouse hepatocytes for the expression of fatty acid elongases that contribute to a waterproof epidermis, suggesting that this pathway is conserved through evolution. This developmental switch in Drosophila lipid metabolism promotes lifespan and desiccation resistance in adults and suppresses hallmarks of diabetes, including elevated glucose levels and intolerance to dietary sugars. These studies establish dHNF4 as a regulator of the adult metabolic state.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Metabolismo Energético/fisiologia , Fator 4 Nuclear de Hepatócito/metabolismo , Homeostase/fisiologia , Metabolismo dos Lipídeos/fisiologia , Animais , Drosophila melanogaster/crescimento & desenvolvimento , Ácidos Graxos/metabolismo
11.
EMBO J ; 31(5): 1253-65, 2012 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-22227521

RESUMO

Systemic wound response (SWR) through intertissue communication in response to local wounds is an essential biological phenomenon that occurs in all multicellular organisms from plants to animals. However, our understanding of SWR has been greatly hampered by the complexity of wound signalling communication operating within the context of an entire organism. Here, we show genetic evidence of a redox-dependent SWR from the wound site to remote tissues by identifying critical genetic determinants of SWR. Local wounds in the integument rapidly induce activation of a novel circulating haemolymph serine protease, Hayan, which in turn converts pro-phenoloxidase (PPO) to phenoloxidase (PO), an active form of melanin-forming enzyme. The Haemolymph Hayan-PO cascade is required for redox-dependent activation of the c-Jun N-terminal kinase (JNK)-dependent cytoprotective program in neuronal tissues, thereby achieving organism level of homeostasis to resist local physical trauma. These results imply that the PO-activating enzyme cascade, which is a prominent defense system in humoral innate immunity, also mediates redox-dependent SWR, providing a novel link between wound response and the nervous system.


Assuntos
Drosophila/enzimologia , Monofenol Mono-Oxigenase/metabolismo , Serina Proteases/metabolismo , Animais , Drosophila/fisiologia , Hemolinfa/enzimologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Oxirredução , Cicatrização
12.
Dev Cell ; 16(3): 386-97, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19289084

RESUMO

All metazoan guts are in constant contact with diverse food-borne microorganisms. The signaling mechanisms by which the host regulates gut-microbe interactions, however, are not yet clear. Here, we show that phospholipase C-beta (PLCbeta) signaling modulates dual oxidase (DUOX) activity to produce microbicidal reactive oxygen species (ROS) essential for normal host survival. Gut-microbe contact rapidly activates PLCbeta through Galphaq, which in turn mobilizes intracellular Ca(2+) through inositol 1,4,5-trisphosphate generation for DUOX-dependent ROS production. PLCbeta mutant flies had a short life span due to the uncontrolled propagation of an essential nutritional microbe, Saccharomyces cerevisiae, in the gut. Gut-specific reintroduction of the PLCbeta restored efficient DUOX-dependent microbe-eliminating capacity and normal host survival. These results demonstrate that the Galphaq-PLCbeta-Ca(2+)-DUOX-ROS signaling pathway acts as a bona fide first line of defense that enables gut epithelia to dynamically control yeast during the Drosophila life cycle.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/imunologia , Drosophila/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , NADPH Oxidases/metabolismo , Fosfolipase C beta/metabolismo , Animais , Animais Geneticamente Modificados , Sinalização do Cálcio , Linhagem Celular , Sistema Digestório/imunologia , Sistema Digestório/metabolismo , Sistema Digestório/microbiologia , Drosophila/genética , Proteínas de Drosophila/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Imunidade Inata , Inositol 1,4,5-Trifosfato/biossíntese , Modelos Biológicos , Fosfolipase C beta/genética , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/imunologia , Transdução de Sinais
13.
Mol Cells ; 26(6): 606-10, 2008 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-18852525

RESUMO

Phenoloxidase (PO), a melanin-forming enzyme around the foreign bodies, is an important component of the host defense system in invertebrates. Pro-PO is the enzymatically inactive zymogen form of PO. In the Drosophila genome, three Pro-PO isoforms have been identified to date. These include Pro-PO1 and 2, which are primarily expressed in crystal cells, and Pro-PO3, which is predominantly found in the lamellocytes. In this study, we demonstrated that Drosophila Pro-PO3, but not Pro-PO1 or 2, is enzymatically active in its zymogen form. These findings were evidenced by spectacular melanin forming capacities of various cells and tissues that overexpressed these proenzymes. Furthermore, the melanization phenotype observed in the lamellocyte-enriched hop(Tum-1) mutant was drastically reduced in the absence of PPO3, indicating that PPO3 plays a major role in the lamellocyte-mediated spontaneous melanization process. Taken together, these findings indicate that the biochemical properties, activation mode and in vivo role of Pro-PO3 are likely distinct from those of the other two Pro-PO enzymes involved in Drosophila physiology.


Assuntos
Catecol Oxidase/metabolismo , Precursores Enzimáticos/metabolismo , Hemócitos/fisiologia , Melaninas/metabolismo , Animais , Drosophila/enzimologia , Ativação Enzimática
14.
BMB Rep ; 41(2): 102-7, 2008 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-18315944

RESUMO

Extracellular proteases play an important role in a wide range of host physiological events, such as food digestion, extracellular matrix degradation, coagulation and immunity. Among the large extracellular protease family, serine proteases that contain a "paper clip"-like domain and are therefore referred to as CLIP-domain serine protease (clip-SP), have been found to be involved in unique biological processes, such as immunity and development. Despite the increasing amount of biochemical information available regarding the structure and function of clip-SPs, their in vivo physiological significance is not well known due to a lack of genetic studies. Recently, Drosophila has been shown to be a powerful genetic model system for the dissection of biological functions of the clip-SPs at the organism level. Here, the current knowledge regarding Drosophila clip-SPs has been summarized and future research directions to evaluate the role that clip-SPs play in Drosophila immunity are discussed.


Assuntos
Drosophila/enzimologia , Drosophila/imunologia , Imunidade Inata , Serina Endopeptidases/fisiologia , Animais , Estrutura Terciária de Proteína
15.
Curr Biol ; 16(8): 808-13, 2006 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-16631589

RESUMO

Unlike mammalian Toll-like Receptors, the Drosophila Toll receptor does not interact directly with microbial determinants but is rather activated upon binding a cleaved form of the cytokine-like molecule Spatzle (Spz). During the immune response, Spz is thought to be processed by secreted serine proteases (SPs) present in the hemolymph that are activated by the recognition of gram-positive bacteria or fungi . In the present study, we have used an in vivo RNAi strategy to inactivate 75 distinct Drosophila SP genes. We then screened this collection for SPs regulating the activation of the Toll pathway by gram-positive bacteria. Here, we report the identification of five novel SPs that function in an extracellular pathway linking the recognition proteins GNBP1 and PGRP-SA to Spz. Interestingly, four of these genes are also required for Toll activation by fungi, while one is specifically associated with signaling in response to gram-positive bacterial infections. These results demonstrate the existence of a common cascade of SPs upstream of Spz, integrating signals sent by various secreted recognition molecules via more specialized SPs.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/imunologia , Serina Endopeptidases/fisiologia , Receptores Toll-Like/metabolismo , Animais , Proteínas de Transporte/metabolismo , Enterococcus faecalis , Infecções por Bactérias Gram-Positivas/imunologia , Micrococcus luteus , Interferência de RNA , Serina Endopeptidases/genética
16.
Dev Cell ; 10(1): 45-55, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16399077

RESUMO

The Toll receptor was originally identified as an indispensable molecule for Drosophila embryonic development and subsequently as an essential component of innate immunity from insects to humans. Although in Drosophila the Easter protease processes the pro-Spätzle protein to generate the Toll ligand during development, the identification of the protease responsible for pro-Spätzle processing during the immune response has remained elusive for a decade. Here, we report a protease, called Spätzle-processing enzyme (SPE), required for Toll-dependent antimicrobial response. Flies with reduced SPE expression show no noticeable pro-Spätzle processing and become highly susceptible to microbial infection. Furthermore, activated SPE can rescue ventral and lateral development in embryos lacking Easter, showing the functional homology between SPE and Easter. These results imply that a single ligand/receptor-mediated signaling event can be utilized for different biological processes, such as immunity and development, by recruiting similar ligand-processing proteases with distinct activation modes.


Assuntos
Proteínas de Drosophila/metabolismo , Imunidade/fisiologia , Serina Endopeptidases/fisiologia , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo , Animais , Animais Geneticamente Modificados , Linhagem Celular , Drosophila/imunologia , Proteínas de Drosophila/deficiência , Embrião não Mamífero/metabolismo , Indução Embrionária , Ativação Enzimática , Corpo Adiposo/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Modelos Biológicos , Dados de Sequência Molecular , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , RNA Mensageiro/biossíntese , Proteínas Recombinantes/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Homologia de Sequência de Aminoácidos , Fatores de Tempo
17.
Mol Cell Biol ; 24(1): 172-85, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14673153

RESUMO

In Drosophila melanogaster, although the NF-kappaB transcription factors play a pivotal role in the inducible expression of innate immune genes, such as antimicrobial peptide genes, the exact regulatory mechanism of the tissue-specific constitutive expression of these genes in barrier epithelia is largely unknown. Here, we show that the Drosophila homeobox gene product Caudal functions as the innate immune transcription modulator that is responsible for the constitutive local expression of antimicrobial peptides cecropin and drosomycin in a tissue-specific manner. These results suggest that certain epithelial tissues have evolved a unique constitutive innate immune strategy by recruiting a developmental "master control" gene.


Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Drosophila melanogaster/genética , Epitélio/metabolismo , Proteínas de Homeodomínio/genética , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Proteínas de Drosophila , Drosophila melanogaster/metabolismo , Proteínas de Homeodomínio/metabolismo , Imunidade Inata/fisiologia , Regiões Promotoras Genéticas , Fatores de Transcrição
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