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1.
Cell Rep ; 40(10): 111265, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36070689

RESUMO

Germline Argonautes direct transcriptome surveillance within perinuclear membraneless organelles called nuage. In C. elegans, a family of Vasa-related Germ Line Helicase (GLH) proteins localize in and promote the formation of nuage. Previous studies have implicated GLH proteins in inherited silencing, but direct roles in small-RNA production, Argonaute binding, or mRNA targeting have not been identified. Here we show that GLH proteins compete with each other to control Argonaute pathway specificity, bind directly to Argonaute target mRNAs, and promote the amplification of small RNAs required for transgenerational inheritance. We show that the ATPase cycle of GLH-1 regulates direct binding to the Argonaute WAGO-1, which engages amplified small RNAs. Our findings support a dynamic and direct role for GLH proteins in inherited silencing beyond their role as structural components of nuage.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , RNA Helicases DEAD-box/metabolismo , Células Germinativas/metabolismo , RNA Mensageiro/metabolismo
2.
Cell Commun Signal ; 20(1): 135, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050770

RESUMO

BACKGROUND: Nuclear hormone receptors are involved in transcriptional regulation and many important cellular processes including development and metabolism. However, its role in DNA damage-induced apoptosis remains elusive. METHODS: Synchronized young adult animals were irradiated with different doses of gamma-Ray, and then put back to culture at 20 °C. Germline cell apoptosis was scored at different time point. RESULTS: Deletion of nhr-14 led to decreased DNA damage-induced germline apoptosis, but not the physiological programmed cell death. We also demonstrate that nhr-14 functions downstream of the DNA damage checkpoint pathway. Moreover, we show that nhr-14 regulates egl-1 and ced-13 transcription upon DNA damage. Mechanistically, NHR-14 forms a complex with CEP-1/p53 and binds directly to the egl-1 promoter to promote egl-1 transcription.. CONCLUSIONS: Our results indicate that NHR-14/HNF4α cooperates with CEP-1/p53 to regulate DNA damage-induced apoptosis. Video abstract.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Apoptose , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Dano ao DNA , Proteína Supressora de Tumor p53/metabolismo
3.
Mol Syst Biol ; 18(9): e10514, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36106925

RESUMO

Efficient navigation based on chemical cues is an essential feature shared by all animals. These cues may be encountered in complex spatiotemporal patterns and with orders of magnitude varying intensities. Nevertheless, sensory neurons accurately extract the relevant information from such perplexing signals. Here, we show how a single sensory neuron in Caenorhabditis elegans animals can cell-autonomously encode complex stimulus patterns composed of instantaneous sharp changes and of slowly changing continuous gradients. This encoding relies on a simple negative feedback in the G-protein-coupled receptor (GPCR) signaling pathway in which TAX-6/Calcineurin plays a key role in mediating the feedback inhibition. This negative feedback supports several important coding features that underlie an efficient navigation strategy, including exact adaptation and adaptation to the magnitude of the gradient's first derivative. A simple mathematical model explains the fine neural dynamics of both wild-type and tax-6 mutant animals, further highlighting how the calcium-dependent activity of TAX-6/Calcineurin dictates GPCR inhibition and response dynamics. As GPCRs are ubiquitously expressed in all sensory neurons, this mechanism may be a general solution for efficient cell-autonomous coding of external stimuli.


Assuntos
Calcineurina , Cálcio , Animais , Caenorhabditis elegans/metabolismo , Calcineurina/metabolismo , Cálcio/metabolismo , Retroalimentação , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/metabolismo
4.
Elife ; 112022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36098634

RESUMO

Gap-junctional signaling mediates myriad cellular interactions in metazoans. Yet, how gap junctions control the positioning of cells in organs is not well understood. Innexins compose gap junctions in invertebrates and affect organ architecture. Here, we investigate the roles of gap-junctions in controlling distal somatic gonad architecture and its relationship to underlying germline stem cells in Caenorhabditis elegans. We show that a reduction of soma-germline gap-junctional activity causes displacement of distal sheath cells (Sh1) towards the distal end of the gonad. We confirm, by live imaging, transmission electron microscopy, and antibody staining, that bare regions-lacking somatic gonadal cell coverage of germ cells-are present between the distal tip cell (DTC) and Sh1, and we show that an innexin fusion protein used in a prior study encodes an antimorphic gap junction subunit that mispositions Sh1. We determine that, contrary to the model put forth in the prior study based on this fusion protein, Sh1 mispositioning does not markedly alter the position of the borders of the stem cell pool nor of the progenitor cell pool. Together, these results demonstrate that gap junctions can control the position of Sh1, but that Sh1 position is neither relevant for GLP-1/Notch signaling nor for the exit of germ cells from the stem cell pool.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Células Germinativas/metabolismo , Gônadas/metabolismo , Células-Tronco/metabolismo
5.
PLoS One ; 17(9): e0274076, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36112613

RESUMO

Genetic and environmental manipulations, such as dietary restriction, can improve both health span and lifespan in a wide range of organisms, including humans. Changes in nutrient intake trigger often overlapping metabolic pathways that can generate distinct or even opposite outputs depending on several factors, such as when dietary restriction occurs in the lifecycle of the organism or the nature of the changes in nutrients. Due to the complexity of metabolic pathways and the diversity in outputs, the underlying mechanisms regulating diet-associated pro-longevity are not yet well understood. Adult reproductive diapause (ARD) in the model organism Caenorhabditis elegans is a dietary restriction model that is associated with lengthened lifespan and reproductive potential. To explore the metabolic pathways regulating ARD in greater depth, we performed a candidate-based genetic screen analyzing select nutrient-sensing pathways to determine their contribution to the regulation of ARD. Focusing on the three phases of ARD (initiation, maintenance, and recovery), we found that ARD initiation is regulated by fatty acid metabolism, sirtuins, AMPK, and the O-linked N-acetyl glucosamine (O-GlcNAc) pathway. Although ARD maintenance was not significantly influenced by the nutrient sensors in our screen, we found that ARD recovery was modulated by energy sensing, stress response, insulin-like signaling, and the TOR pathway. Further investigation of downstream targets of NHR-49 suggest the transcription factor influences ARD initiation through the fatty acid ß-oxidation pathway. Consistent with these findings, our analysis revealed a change in levels of neutral lipids associated with ARD entry defects. Our findings identify conserved genetic pathways required for ARD entry and recovery and uncover genetic interactions that provide insight into the role of OGT and OGA.


Assuntos
Diapausa , Insulinas , Sirtuínas , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Ácidos Graxos/metabolismo , Glucosamina/metabolismo , Humanos , Lipídeos , Nutrientes , Sirtuínas/genética , Sirtuínas/metabolismo , Fatores de Transcrição/metabolismo
6.
Gene ; 845: 146776, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36063972

RESUMO

Mutations in the mitochondrial DNA (mtDNA) are closely related to age and age-related complex diseases, but the exact regulatory mechanism of mtDNA natural variation or polymorphism and ageing remains unclear. Recently, nuclear genes that regulate mitochondrial functions and thereby influence ageing have been widely studied. In this study, the relationship between the retrograde communication from the mitochondria to the nucleus and its ultimate effect on ageing has been elucidated. This study found that the natural variations in COX1 of the mitochondria in the Caenorhabditis elegans population do not correlate with multiple phenotypes, except for a mild correlation with lifespan. After excluding the differences in the nuclear genome, the correlation between natural mitochondrial variation and lifespan increased significantly. Moreover, mtDNA variation downregulated the nuclear dct-15 gene expression, which consequently reduced the lifespan, development rate and motility of C. elegans. dct-15 mutations decreased mitochondria copy number but increased ATP content and mitochondrial ultrastructure. Thus, the results indicated that dct-15 interacted with the mitochondrial DNA polymorphisms in COX1 and is associated with ageing. Finally, bioinformatic analyses revealed that mtDNA variation regulated the structural constituent of the cuticle via dct-15 and suggested that the structural constituent of the cuticle could have an important role in the development and ageing processes. These results provide insights into the mtDNA mechanism that can alter the nuclear gene and thereby regulate ageing and ageing-related diseases.


Assuntos
Caenorhabditis elegans , DNA Mitocondrial , Trifosfato de Adenosina/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Longevidade/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo
7.
J Cell Biol ; 221(10)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36069810

RESUMO

The chaperone-mediated sequestration of misfolded proteins into inclusions is a pivotal cellular strategy to maintain proteostasis in Saccharomyces cerevisiae, executed by small heat shock proteins (sHsps) Hsp42 and Btn2. Direct homologs of Hsp42 and Btn2 are absent in other organisms, questioning whether sequestration represents a conserved proteostasis strategy and, if so, which factors are involved. We examined sHsps from Escherchia coli, Caenorhabditis elegans, and humans for their ability to complement the defects of yeast sequestrase mutants. We show that sequestration of misfolded proteins is an original and widespread activity among sHsps executed by specific family members. Sequestrase positive C. elegans' sHsps harbor specific sequence features, including a high content of aromatic and methionine residues in disordered N-terminal extensions. Those sHsps buffer limitations in Hsp70 capacity in C. elegans WT animals and are upregulated in long-lived daf-2 mutants, contributing to lifespan extension. Cellular protection by sequestration of misfolded proteins is, therefore, an evolutionarily conserved activity of the sHsp family.


Assuntos
Evolução Molecular , Proteínas de Choque Térmico Pequenas , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Choque Térmico Pequenas/genética , Proteínas de Choque Térmico Pequenas/metabolismo , Humanos , Dobramento de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
8.
Biochem Biophys Res Commun ; 628: 98-103, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36084557

RESUMO

A cryoprotectant known as ice-binding protein (IBP) is thought to facilitate the cold survival of plants, insects, and fungi. Here, we prepared a genetically modified Caenorhabditis elegans strain to synthesize fish-derived IBPs in its body wall muscles and examined whether the antifreeze activity modification of this IBP by point mutation affects the cold tolerance of this worm. We chose a 65-residue IBP identified from notched-fin eelpout, for which the replacement of the 20th alanine residue (A20) modifies its antifreeze activity. These mutant proteins are denoted A20L, A20G, A20T, A20V, and A20I along with the wild-type (WT) protein. We evaluated the survival rate (%) of the transgenic C. elegans that synthesized each IBP mutant following 24 h of preservation at -5, +2, and +5 °C. Significantly, a dramatic improvement in the survival rate was detected for the worms synthesizing the activity-enhanced mutants (A20T and A20I), especially at +2 °C. In contrast, the rate was not improved by the expression of the defective mutants (A20L, A20G, WT and A20V). The survival rate (%) probably correlates with the antifreeze activity of the IBP. These data suggest that IBP protects the cell membrane by employing its ice-binding mechanism, which ultimately improves the cold tolerance of an IBP-containing animal.


Assuntos
Proteínas Anticongelantes , Gelo , Alanina/genética , Animais , Proteínas Anticongelantes/química , Proteínas Anticongelantes/genética , Proteínas Anticongelantes/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Peixes/genética , Congelamento , Proteínas Mutantes/metabolismo , Mutação , Compostos Organotiofosforados
9.
Dev Cell ; 57(17): 2111-2126.e6, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36049484

RESUMO

Development of the C. elegans gonad has long been studied as a model of organogenesis driven by collective cell migration. A somatic cell named the distal tip cell (DTC) is thought to serve as the leader of following germ cells; yet, the mechanism for DTC propulsion and maneuvering remains elusive. Here, we demonstrate that the DTC is not self-propelled but rather is pushed by the proliferating germ cells. Proliferative pressure pushes the DTC forward, against the resistance of the basement membrane in front. The DTC locally secretes metalloproteases that degrade the impeding membrane, resulting in gonad elongation. Turning of the gonad is achieved by polarized DTC-matrix adhesions. The asymmetrical traction results in a bending moment on the DTC. Src and Cdc42 regulate integrin adhesion polarity, whereas an external netrin signal determines DTC orientation. Our findings challenge the current view of DTC migration and offer a distinct framework to understand organogenesis.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Movimento Celular/fisiologia , Gônadas/metabolismo , Organogênese
10.
J Cell Biol ; 221(10)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36083688

RESUMO

Cell polarity relies on the asymmetric distribution of the conserved PAR proteins, which is regulated by phosphorylation/dephosphorylation reactions. While the kinases involved have been well studied, the role of phosphatases remains poorly understood. In Caenorhabditis elegans zygotes, phosphorylation of the posterior PAR-2 protein by the atypical protein kinase PKC-3 inhibits PAR-2 cortical localization. Polarity establishment depends on loading of PAR-2 at the posterior cortex. We show that the PP1 phosphatases GSP-1 and GSP-2 are required for polarity establishment in embryos. We find that codepletion of GSP-1 and GSP-2 abrogates the cortical localization of PAR-2 and that GSP-1 and GSP-2 interact with PAR-2 via a PP1 docking motif in PAR-2. Mutating this motif in vivo, to prevent binding of PAR-2 to PP1, abolishes cortical localization of PAR-2, while optimizing this motif extends PAR-2 cortical localization. Our data suggest a model in which GSP-1/-2 counteracts PKC-3 phosphorylation of PAR-2, allowing its cortical localization at the posterior and polarization of the one-cell embryo.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Monoéster Fosfórico Hidrolases , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Polaridade Celular , Embrião não Mamífero/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Proteína Quinase C/metabolismo
11.
Elife ; 112022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36094368

RESUMO

The Caenorhabditis elegans adult hermaphrodite germline is surrounded by a thin tube formed by somatic sheath cells that support germ cells as they mature from the stem-like mitotic state through meiosis, gametogenesis, and ovulation. Recently, we discovered that the distal Sh1 sheath cells associate with mitotic germ cells as they exit the niche Gordon et al., 2020. Here, we report that these sheath-associated germ cells differentiate first in animals with temperature-sensitive mutations affecting germ cell state, and stem-like germ cells are maintained distal to the Sh1 boundary. We analyze several markers of the distal sheath, which is best visualized with endogenously tagged membrane proteins, as overexpressed fluorescent proteins fail to localize to distal membrane processes and can cause gonad morphology defects. However, such reagents with highly variable expression can be used to determine the relative positions of the two Sh1 cells, one of which often extends further distal than the other.


Assuntos
Proteínas de Caenorhabditis elegans , Neuroblastoma , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Feminino , Gônadas/metabolismo , Meiose
12.
Int J Mol Sci ; 23(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36077432

RESUMO

Alzheimer's disease (AD) is one of the leading causes of dementia. As the first common neurodegenerative disease, there are no effective drugs that can reverse the progression. The present study is to report the anti-AD effect of cryptotanshinone (CTS), a natural product isolated from Salvia castanea. It is found that it can alleviate AD-like features associated with Aß1-42 toxicity in muscle cells as well as neuronal cells of Caenorhabditis elegans (C. elegans). Further studies showed that CTS reduced the level of reactive oxygen species (ROS) in nematodes, up-regulated the expression of sod-3, and enhanced superoxide dismutase activity. Cryptotanshinone reduced the level of Aß monomers and highly toxic oligomers in C. elegans while inhibiting the abnormal aggregation of polyglutamine protein. In addition, CTS upregulated the expression of hsp-16.2 and downregulated the expression of ace-2. These results suggested that CTS could alleviate oxidative stress and reduce the level of abnormally aggregated proteins and has the potential to be developed as an anti-AD drug candidate.


Assuntos
Doença de Alzheimer , Proteínas de Caenorhabditis elegans , Doenças Neurodegenerativas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Estresse Oxidativo , Fenantrenos , Espécies Reativas de Oxigênio/metabolismo
13.
Oxid Med Cell Longev ; 2022: 5297342, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36017239

RESUMO

Nowadays, human beings are exposed to Cu in varieties of environmental mediums, resulting in health risks needing urgent attention. Our research found that Cu shortened lifespan and induced aging-related phenotypes of Caenorhabditis elegans (C. elegans). Transcriptomics data showed differential expression genes induced by Cu were mainly involved in regulation of metabolism and longevity, especially in fatty acid metabolism. Quantitative detection of free fatty acid by GC/MS further found that Cu upregulated free fatty acids of C. elegans. A mechanism study confirmed that Cu promoted the fat accumulation in nematodes, which was owing to disorder of fatty acid desaturase and CoA synthetase, endoplasmic reticulum unfolded protein response (UPRER), mitochondrial membrane potential, and unfolded protein response (UPRmt). In addition, Cu activated oxidative stress and prevented DAF-16 translocating into nuclear with a concomitant reduction in the expression of environmental stress-related genes. Taken together, the research suggested that Cu promoted aging and induced fat deposition and oxidative damage.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Humanos , Longevidade , Estresse Oxidativo , Transcriptoma/genética
14.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36012413

RESUMO

The number of reported macrocyclic lactones (ML) resistance cases across all livestock hosts is steadily increasing. Different studies in the parasitic nematode Haemonchus contortus assume the participation of cytochrome P450s (Cyps) enzymes in ML resistance. Still, functional data about their individual contribution to resistance or substrate specificity is missing. Via microinjection, transgenic Caenorhabditis elegans expressing HCON_00141052 (transgene-Hco-cyp-13A11) from extrachromosomal arrays were generated. After 24 h of exposure to different concentrations of ivermectin (IVM), ivermectin aglycone (IVMa), selamectin (SEL), doramectin (DRM), eprinomectin (EPR), and moxidectin (MOX), motility assays were performed to determine the impact of the H. contortus Cyp to the susceptibility of the worms against each ML. While transgene-Hco-cyp-13A11 significantly decreased susceptibility to IVM (four-fold), IVMa (2-fold), and SEL (3-fold), a slight effect for DRM and no effect for MOX, and EPR was observed. This substrate specificity of Hco-cyp-13A11 could not be explained by molecular modeling and docking studies. Hco-Cyp-13A11 molecular models were obtained for alleles from isolates with different resistance statuses. Although 14 amino acid polymorphisms were detected, none was resistance specific. In conclusion, Hco-cyp-13A11 decreased IVM, IVMa, and SEL susceptibility to a different extent, but its potential impact on ML resistance is not driven by polymorphisms.


Assuntos
Anti-Helmínticos , Haemonchus , Animais , Animais Geneticamente Modificados , Anti-Helmínticos/farmacologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Resistência a Medicamentos/genética , Haemonchus/genética , Ivermectina/metabolismo , Ivermectina/farmacologia , Lactonas/metabolismo , Lactonas/farmacologia
15.
Sci Rep ; 12(1): 14003, 2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-35977998

RESUMO

Microtubules are fundamental elements of neuronal structure and function. They are dynamic structures formed from protofilament chains of α- and ß-tubulin heterodimers. Acetylation of the lysine 40 (K40) residue of α-tubulin protects microtubules from mechanical stresses by imparting structural elasticity. The enzyme responsible for this acetylation event is MEC-17/αTAT1. Despite its functional importance, however, the consequences of altered MEC-17/αTAT1 levels on neuronal structure and function are incompletely defined. Here we demonstrate that overexpression or loss of MEC-17, or of its functional paralogue ATAT-2, causes a delay in synaptic branch extension, and defective synaptogenesis in the mechanosensory neurons of Caenorhabditis elegans. Strikingly, by adulthood, the synaptic branches in these animals are lost, while the main axon shaft remains mostly intact. We show that MEC-17 and ATAT-2 regulate the stability of the synaptic branches largely independently from their acetyltransferase domains. Genetic analyses reveals novel interactions between both mec-17 and atat-2 with the focal adhesion gene zyx-1/Zyxin, which has previously been implicated in actin remodelling. Together, our results reveal new, acetylation-independent roles for MEC-17 and ATAT-2 in the development and maintenance of neuronal architecture.


Assuntos
Proteínas de Caenorhabditis elegans , Acetilação , Acetiltransferases/genética , Acetiltransferases/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismo
16.
Ecotoxicol Environ Saf ; 243: 114022, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36030687

RESUMO

Exposure to nanoplastics can induce toxicity on organisms at both parental generation (P0-G) and the offspring. However, the underlying mechanism remains unknown. Using Caenorhabditis elegans as a model organism, exposure to 20-nm polystyrene nanoparticle (PS-NP) (1-100 µg/L) upregulated the expressions of insulin ligands (INS-39, INS-3, and DAF-28), and this increase could be further detected in the offspring after PS-NP exposure. Germline ins-39, ins-3, and daf-28 RNAi induced resistance to transgenerational toxicity of PS-NP, indicating that increase in expression of these three insulin ligands mediated induction of transgenerational toxicity. These three insulin ligands transgenerationally activated function of insulin receptor DAF-2 to control transgenerational toxicity of PS-NP. Exposure to 1-100 µg/L PS-NP further upregulated DAF-2, AGE-1, and AKT-1 expressions and downregulated DAF-16 expression. During transgenerational toxicity control, DAF-16/AKT-1/AGE-1 was identified as downstream signaling cascade of DAF-2. Moreover, transcriptional factor DAF-16 activated two downstream targets of HSP-6 (a mitochondrial UPR marker) and SOD-3 (a mitochondrial SOD) to modulate transgenerational toxicity of PS-NP. Our findings indicate a crucial link between activation of insulin signaling and induction of transgenerational toxicity of nanoplastics at low concentrations in organisms.


Assuntos
Proteínas de Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Células Germinativas/metabolismo , Insulina/metabolismo , Ligantes , Microplásticos , Poliestirenos/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Superóxido Dismutase/metabolismo
17.
PLoS Genet ; 18(8): e1010328, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35913999

RESUMO

FOXO transcription factors have been shown to regulate longevity in model organisms and are associated with longevity in humans. To gain insight into how FOXO functions to increase lifespan, we examined the subcellular localization of DAF-16 in C. elegans. We show that DAF-16 is localized to endosomes and that this endosomal localization is increased by the insulin-IGF signaling (IIS) pathway. Endosomal localization of DAF-16 is modulated by endosomal trafficking proteins. Disruption of the Rab GTPase activating protein TBC-2 increases endosomal localization of DAF-16, while inhibition of TBC-2 targets, RAB-5 or RAB-7 GTPases, decreases endosomal localization of DAF-16. Importantly, the amount of DAF-16 that is localized to endosomes has functional consequences as increasing endosomal localization through mutations in tbc-2 reduced the lifespan of long-lived daf-2 IGFR mutants, depleted their fat stores, and DAF-16 target gene expression. Overall, this work identifies endosomal localization as a mechanism regulating DAF-16 FOXO, which is important for its functions in metabolism and aging.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Longevidade , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/genética , Proteínas Ativadoras de GTPase/genética , Humanos , Insulina/metabolismo , Longevidade/genética , Mutação , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
18.
PLoS Genet ; 18(8): e1010348, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35960773

RESUMO

Epithelial cells secrete apical extracellular matrices to form protruding structures such as denticles, ridges, scales, or teeth. The mechanisms that shape these structures remain poorly understood. Here, we show how the actin cytoskeleton and a provisional matrix work together to sculpt acellular longitudinal alae ridges in the cuticle of adult C. elegans. Transient assembly of longitudinal actomyosin filaments in the underlying lateral epidermis accompanies deposition of the provisional matrix at the earliest stages of alae formation. Actin is required to pattern the provisional matrix into longitudinal bands that are initially offset from the pattern of longitudinal actin filaments. These bands appear ultrastructurally as alternating regions of adhesion and separation within laminated provisional matrix layers. The provisional matrix is required to establish these demarcated zones of adhesion and separation, which ultimately give rise to alae ridges and their intervening valleys, respectively. Provisional matrix proteins shape the alae ridges and valleys but are not present within the final structure. We propose a morphogenetic mechanism wherein cortical actin patterns are relayed to the laminated provisional matrix to set up distinct zones of matrix layer separation and accretion that shape a permanent and acellular matrix structure.


Assuntos
Actinas , Caenorhabditis elegans , Actinas/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Citoesqueleto/genética , Matriz Extracelular/metabolismo , Morfogênese
19.
PLoS Genet ; 18(8): e1010115, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35984862

RESUMO

The fine-tuning of gene expression is critical for all cellular processes; aberrations in this activity can lead to pathology, and conversely, resilience. As their role in coordinating organismal responses to both internal and external factors have increasingly come into focus, small non-coding RNAs have emerged as an essential component to disease etiology. Using Systemic RNA interference Defective (SID) mutants of the nematode Caenorhabditis elegans, deficient in gene silencing, we examined the potential consequences of dysfunctional epigenomic regulation in the context of Parkinson's disease (PD). Specifically, the loss of either the sid-1 or sid-3 genes, which encode a dsRNA transporter and an endocytic regulatory non-receptor tyrosine kinase, respectively, conferred neuroprotection to dopaminergic (DA) neurons in an established transgenic C. elegans strain wherein overexpression of human α-synuclein (α-syn) from a chromosomally integrated multicopy transgene causes neurodegeneration. We further show that knockout of a specific microRNA, mir-2, attenuates α-syn neurotoxicity; suggesting that the native targets of mir-2-dependent gene silencing represent putative neuroprotective modulators. In support of this, we demonstrated that RNAi knockdown of multiple mir-2 targets enhanced α-syn-induced DA neurodegeneration. Moreover, we demonstrate that mir-2 overexpression originating in the intestine can induce neurodegeneration of DA neurons, an effect that was reversed by pharmacological inhibition of SID-3 activity. Interestingly, sid-1 mutants retained mir-2-induced enhancement of neurodegeneration. Transcriptomic analysis of α-syn animals with and without a sid-1 mutation revealed 27 differentially expressed genes with human orthologs related to a variety of diseases, including PD. Among these was pgp-8, encoding a P-glycoprotein-related ABC transporter. Notably, sid-1; pgp-8 double mutants abolished the neurodegeneration resulting from intestinal mir-2 overexpression. This research positions known regulators of small RNA-dependent gene silencing within a framework that facilitates mechanistic evaluation of epigenetic responses to exogenous and endogenous factors influencing DA neurodegeneration, revealing a path toward new targets for therapeutic intervention of PD.


Assuntos
Proteínas de Caenorhabditis elegans , Doença de Parkinson , Morte Súbita do Lactente , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Humanos , Doença de Parkinson/patologia , Interferência de RNA , RNA de Cadeia Dupla/metabolismo , Morte Súbita do Lactente/genética , Morte Súbita do Lactente/patologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
20.
Nat Commun ; 13(1): 4883, 2022 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-35986016

RESUMO

How animals rewire cellular programs to survive cold is a fascinating problem with potential biomedical implications, ranging from emergency medicine to space travel. Studying a hibernation-like response in the free-living nematode Caenorhabditis elegans, we uncovered a regulatory axis that enhances the natural resistance of nematodes to severe cold. This axis involves conserved transcription factors, DAF-16/FoxO and PQM-1, which jointly promote cold survival by upregulating FTN-1, a protein related to mammalian ferritin heavy chain (FTH1). Moreover, we show that inducing expression of FTH1 also promotes cold survival of mammalian neurons, a cell type particularly sensitive to deterioration in hypothermia. Our findings in both animals and cells suggest that FTN-1/FTH1 facilitates cold survival by detoxifying ROS-generating iron species. We finally show that mimicking the effects of FTN-1/FTH1 with drugs protects neurons from cold-induced degeneration, opening a potential avenue to improved treatments of hypothermia.


Assuntos
Proteínas de Caenorhabditis elegans , Hipotermia , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ferritinas/genética , Ferritinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Ferro/metabolismo , Mamíferos/metabolismo , Camundongos , Neurônios/metabolismo
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