Zhou Y et al. (2017) Genetics "Potential Nematode Alarm Pheromone Induces Acute Avoidance in Caenorhabditis elegans."

Butcher RA, Zhong W, Jung SK, Choi Y, Nguyen JK, Shou Q, Loeza-Cabrera M, Liu Z, Zhou Y, Aleman-Meza B

[Genetics, 2017]

It is crucial for animal survival to detect dangers such as predators. A good indicator of dangers is injury of conspecifics. Here we show that fluids released from injured conspecifics invoke acute avoidance in both free-living and parasitic nematodes. Caenorhabditis elegans avoids extracts from closely related nematode species but not fruit fly larvae. The worm extracts have no impact on animal lifespan, suggesting that the worm extract may function as an alarm instead of inflict physical harm. Avoidance of the worm extract requires the function of a cGMP signaling pathway that includes the cGMP-gated channel TAX-2/TAX-4 in the amphid sensory neurons ASI and ASK. Genetic evidence indicates that the avoidance behavior is modulated by the neurotransmitters GABA and serotonin, two common targets of anxiolytic drugs. Together, these data support a model that nematodes use a nematode-specific alarm pheromone to detect conspecific injury.

Zhou Y et al. (2018) ACS Chem Biol "Tryptophan Metabolism in Caenorhabditis elegans Links Aggregation Behavior to Nutritional Status."

Butcher RA, Zhou Y, Zhang X

[ACS Chem Biol, 2018]

Caenorhabditis elegans uses aggregation pheromones to communicate its nutritional status and recruit fellow members of its species to food sources. These aggregation pheromones include the IC-ascarosides, ascarosides modified with an indole-3-carbonyl (IC) group on the 4'-position of the ascarylose sugar. Nothing is known about the biosynthesis of the IC modification beyond the fact that it is derived from tryptophan. Here, we show that C. elegans produces endogenously several indole-containing metabolites, including indole-3-pyruvic acid (IPA), indole-3-acetic acid (IAA; auxin), and indole-3-carboxylic acid, and that these metabolites are intermediates in the biosynthetic pathway from tryptophan to the IC group. Stable isotope-labeled IPA and IAA are incorporated into the IC-ascarosides. Importantly, we show that flux through the biosynthetic pathway is affected by the activity of the pyruvate dehydrogenase complex (PDC). Knockdown of the PDC by RNA interference leads to an accumulation of upstream metabolites and a reduction in downstream metabolites in the pathway. Our results show that production of aggregation pheromones is linked to PDC activity and that aggregation behavior may reflect a favorable metabolic state in the worm. Lastly, we show that treatment of C. elegans with indole-containing metabolites in the pathway induces the biosynthesis of the IC-ascarosides. Because the natural environment of C. elegans is rotting plant material, indole-containing metabolites in this environment could potentially stimulate pheromone biosynthesis and aggregation behavior in the worm. Thus, there may be important links between tryptophan metabolism in C. elegans and in plants and bacteria that enable interkingdom signaling.

Zhou Y et al. (2024) Environ Res "2,4,6-trinitrotoluene causes mitochondrial toxicity in Caenorhabditis elegans by affecting electron transport."

Wang C, Xu A, Nie Y, Wu L, Zhou Y

[Environ Res, 2024]

As a typical energetic compound widely used in military activities, 2,4,6-trinitrotoluene (TNT) has attracted great attention in recent years due to its heavy pollution and wide distribution in and around the training facilities, firing ranges, and demolition sites. However, the subcellular targets and the underlying toxic mechanism of TNT remain largely unknown. In this study, we explored the toxic effects of TNT biological reduction on the mitochondrial function and homeostasis in Caenorhabditis elegans (C. elegans). With short-term exposure of L4 larvae, 10-1000 ng/mL TNT reduced mitochondrial membrane potential and adenosine triphosphate (ATP) content, which was associated with decreased expression of specific mitochondrial complex involving gas-1 and mev-1 genes. Using fluorescence-labeled transgenic nematodes, we found that fluorescence expression of sod-3 (muls84) and gst-4 (dvls19) was increased, suggesting that TNT disrupted the mitochondrial antioxidant defense system. Furthermore, 10 ng/mL TNT exposure increased the expression of the autophagy-related gene pink-1 and activated mitochondrial unfolded protein response (mt UPR), which was indicated by the increased expression of mitochondrial stress activated transcription factor atfs-1, ubiquitin-like protein ubl-5, and homeobox protein dve-1. Our findings demonstrated that TNT biological reduction caused mitochondrial dysfunction and the development of mt UPR protective stress responses, and provided a basis for determining the potential risks of energetic compounds to living organisms.

Zhou Y et al. (2019) Nat Commun "A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing."

Shen Y, Peng G, He Z, Song M, Jing N, Zhou Y, Wang X, Dieterich C, Antebi A, Cui G

[Nat Commun, 2019]

Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83/miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans. Upregulated in the intestine by hsf-1/HSF1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5/MCOLN, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity. These findings thus identify a microRNA-based mechanism to coordinate the decreasing macroautophagy in various tissues with age.

Zhou Y et al. (2015) J Lipid Res "Role of CYP eicosanoids in the regulation of pharyngeal pumping and food uptake in Caenorhabditis elegans."

Falck JR, Menzel R, Rothe M, Schunck WH, Zhou Y

[J Lipid Res, 2015]

Cytochrome P450 (CYP)-dependent eicosanoids comprise epoxy- and hydroxy-metabolites of long-chain PUFAs (LC-PUFAs). In mammals, CYP eicosanoids contribute to the regulation of cardiovascular and renal function. Caenorhabditis elegans produces a large set of CYP eicosanoids; however, their role in worm's physiology is widely unknown. Mutant strains deficient in LC-PUFA/eicosanoid biosynthesis displayed reduced pharyngeal pumping frequencies. This impairment was rescued by long-term eicosapentaenoic and/or arachidonic acid supplementation, but not with a nonmetabolizable LC-PUFA analog. Short-term treatment with 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), the most abundant CYP eicosanoid in C. elegans, was as effective as long-term LC-PUFA supplementation in the mutant strains. In contrast, 20-HETE caused decreased pumping frequencies. The opposite effects of 17,18-EEQ and 20-HETE were mirrored by the actions of neurohormones. 17,18-EEQ mimicked the stimulating effect of serotonin when added to starved worms, whereas 20-HETE shared the inhibitory effect of octopamine in the presence of abundant food. In wild-type worms, serotonin increased free 17,18-EEQ levels, whereas octopamine selectively induced the synthesis of hydroxy-metabolites. These results suggest that CYP eicosanoids may serve as second messengers in the regulation of pharyngeal pumping and food uptake in C. elegans.

Zhou Y et al. (2018) Elife "Biosynthetic tailoring of existing ascaroside pheromones alters their biological function in C. elegans."

Jones Lipinski RA, Zhou Y, Bhar S, Feng L, Wang Y, Butcher RA, Zhang X, Han J

[Elife, 2018]

<i>Caenorhabditis elegans</i> produces ascaroside pheromones to control its development and behavior. Even minor structural differences in the ascarosides have dramatic consequences for their biological activities. Here, we identify a mechanism that enables <i>C. elegans</i> to dynamically tailor the fatty-acid side chains of the indole-3-carbonyl (IC)-modified ascarosides it has produced. In response to starvation, <i>C. elegans</i> uses the peroxisomal acyl-CoA synthetase ACS-7 to activate the side chains of medium-chain IC-ascarosides for -oxidation involving the acyl-CoA oxidases ACOX-1.1 and ACOX-3. This pathway rapidly converts a favorable ascaroside pheromone that induces aggregation to an unfavorable one that induces the stress-resistant dauer larval stage. Thus, the pathway allows the worm to respond to changing environmental conditions and alter its chemical message without having to synthesize new ascarosides de novo. We establish a new model for biosynthesis of the IC-ascarosides in which side-chain -oxidation is critical for controlling the type of IC-ascarosides produced.

Zhou Y et al. (2015) Biomaterials "A real-time documentation and mechanistic investigation of quantum dots-induced autophagy in live Caenorhabditis elegans."

Su Y, Wu S, Wang Q, Zhang H, Song B, Zhou Y, He Y

[Biomaterials, 2015]

Autophagy is a highly important intracellular process for the degradation of endogenous or foreign contents in the cytoplasm. Though nanomaterials-induced autophagy has been extensively studied, real-time information about the autophagic process induced by nanomaterials in live organisms remains unknown. Here by using Caenorhabditis elegans as the model organism and fluorescent semiconductor quantum dots (QDs) as a representative nanomaterial, we systematically investigated the phenomenon of QDs-induced autophagy in live organisms. Our results demonstrated that the internalized QDs trigger a complete autophagic process in C.elegans intestinal cells. Further investigations revealed that this QD-induced autophagy in C.elegans is neither a response to released heavy metal ions by the QDs, nor an attempt to engulf exogenous QD materials, but a defensive strategy of the organism to clear and recycle damaged endosomes. Of particular significance, for the first time, we presented real-time tracking of autophagosomes formation in live organisms, providing detailed temporal-spatial information of this process. This study may help us better understand the relationship between nanomaterials and autophagy invivo, and provide invaluable information for safety evaluation and bio-application of nanomaterials.

Zhou Y et al. (2024) Free Radic Biol Med "Superoxide signal orchestrates tetrathiomolybdate-induced longevity via ARGK-1 in Caenorhabditis elegans."

Wei F, Liu L, Duan Z, Zhou Y, Zhang M, Lu S, Li G

[Free Radic Biol Med, 2024]

Purpose: While reactive oxygen species (ROS) have been identified as key redox signaling agents contributing to aging process, which and how specific oxidants trigger healthy longevity remain unclear. This paper aimed to explore the precise role and signaling mechanism of superoxide (O2-) in health and longevity.Methods: A tool for precise regulation of O2- levels in vivo was developed based on the inhibition of superoxide dismutase 1 (SOD1) by tetrathiomolybdate (TM) in C. elegans. Then, we examined the effects of TM on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the signaling mechanism for longevity induced by TM-O2- was screened by transcriptome analysis and tested in sod-1 and argk-1 RNAi strains, sod-2, sod-3, and daf-16 mutants.Results: TM promoted longevity in C. elegans with a concomitant extension of healthy lifespan as indicated by increasing fertility and mobility and reducing lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanically, TM could precisely regulate O2- levels in nematodes via modulating superoxide dismutase 1 activity. An O2- scavenger Mn(III)TBAP abolished TM-induced lifespan extension, while an O2- generator paraquat at low concentration mimicked the life prolongation effects. The longevity in TM-treated worms was abolished by sod-1 RNAi but was not affected in sod-2 or sod-3 mutants. Further transcriptome analysis revealed arginine kinase ARGK-1 and its downstream insulin/insulin-like growth factor 1 signaling (IIS) as potential effectors for TM-O2-induced longevity, and argk-1 RNAi or daf-16 mutant nullified the longevity.Conclusions: These findings indicate that it is feasible to precisely control specific oxidant in vivo and O2- orchestrates TM-induced health and longevity in C. elegans via ARGK-1-IIS axis.

Zhou Y et al. (2024) PLoS Pathog "Collagen and actin network mediate antiviral immunity against Orsay virus in C. elegans intestinal cells."

Zhou Y, Chen H, Tao YJ, Zhong W

[PLoS Pathog, 2024]

C. elegans is a free-living nematode that is widely used as a small animal model for studying fundamental biological processes and disease mechanisms. Since the discovery of the Orsay virus in 2011, C. elegans also holds the promise of dissecting virus-host interaction networks and innate antiviral immunity pathways in an intact animal. Orsay virus primarily targets the worm intestine, causing enlarged intestinal lumen as well as visible changes to infected cells such as liquefaction of cytoplasm and convoluted apical border. Previous studies of Orsay virus identified that C. elegans is able to mount antiviral responses by DRH-1/RIG-I mediated RNA interference and Intracellular Pathogen Response, a uridylyltransferase that destabilizes viral RNAs by 3' end uridylation, and ubiquitin protein modifications and turnover. To comprehensively search for novel antiviral pathways in C. elegans, we performed genome-wide RNAi screens by bacterial feeding using existing bacterial RNAi libraries covering 94% of the entire genome. Out of the 106 potential antiviral gene hits identified, we investigated those in three new pathways: collagens, actin remodelers, and epigenetic regulators. By characterizing Orsay virus infection in RNAi and mutant worms, our results indicate that collagens likely form a physical barrier in intestine cells to inhibit viral infection by preventing Orsay virus entry. Furthermore, evidence suggests that actin remodeling proteins (unc-34, wve-1 and wsp-1) and chromatin remodelers (nurf-1 and isw-1) exert their antiviral activities by regulating the intestinal actin (act-5), a critical component of the terminal web which likely function as another physical barrier to prevent Orsay infection.

Zhou Y et al. (2018) Food Funct "Stress resistance and lifespan extension of Caenorhabditis elegans enhanced by peptides from mussel (Mytilus edulis) protein hydrolyzate."

Zhou Y, Zhou X, Song S, Xu Q, Zhu B

[Food Funct, 2018]

Bioactive peptides derived from mussels have multiple healthcare functions. Herein, we aimed to examine the effects of mussel peptide preparation on lifespan, stress resistance, apoptosis and aging in Caenorhabditis elegans. Lifespan was determined by counting the number of surviving nematodes daily. ROS level and lipofuscin were measured using a fluorescent microscope. The mussel protein was prepared and hydrolyzed, and then fractionated by ultrafiltration. The fraction (&lt;3 kDa) was purified by gel filtration to obtain the bioactive peptides, and the peptide sequences included in the fractions were identified, which were mostly composed of peptides with &lt;20 amino acid residues. Mussel peptides treatment was found to significantly increase oxidative stress resistance and extend the lifespan of C. elegans. Moreover, this treatment also reduced endogenous ROS level and aging pigments accumulation in C. elegans as well as apoptosis. Collectively, these findings demonstrated that mussel peptides could contribute to healthspan extension of C. elegans through regulating mRNA expression of daf-2 and daf-16. These results highlighted the important role of mussel peptides for food and pharmaceutical industries to develop new nutraceuticals and functional foods.