Wang Y et al. (2015) Science "Mitochondrial dysfunction and longevity in animals: Untangling the knot."

Wang Y, Hekimi S

[Science, 2015]

Mitochondria generate adenosine 5'-triphosphate (ATP) and are a source of potentially toxic reactive oxygen species (ROS). It has been suggested that the gradual mitochondrial dysfunction that is observed to accompany aging could in fact be causal to the aging process. Here we review findings that suggest that age-dependent mitochondrial dysfunction is not sufficient to limit life span. Furthermore, mitochondrial ROS are not always deleterious and can even stimulate pro-longevity pathways. Thus, mitochondrial dysfunction plays a complex role in regulating longevity.

Wang Y et al. (2006) FASEB J "C. elegans STAT: evolution of a regulatory switch."

Wang Y, Levy DE

[FASEB J, 2006]

STAT transcription factors have been implicated in many biological processes, particularly host immune defense and development. Here we characterize a STAT orthologue from the nematode, C. elegans. We show that this protein, termed STA-1, is structurally and functionally related to other vertebrate and invertebrate STAT proteins, recognizing a cis DNA element conserved through phylogeny. Unexpectedly, STA-1 lacks the conserved amino-terminal oligomerization domain found in vertebrate and other invertebrate STAT proteins, a feature also lacking in orthologues from a distantly related nematode species and from the slime mold, Dictyostelium discoideum. This absence suggests that a primordial STAT protein lacked this domain, which was accreted later in evolution to provide further regulatory control of STAT signaling. Derivation of null mutants demonstrated that STA-1 is not required for nematode viability, despite its widespread expression in multiple tissues of the worm. However, mutant STA-1 proteins that lack functional coiled-coil and DNA binding domains could still be activated and accumulated in the nucleus, suggesting that DNA binding is not a necessary prerequisite for nuclear retention of activated STAT proteins. Our results shed new light on the evolution and function of the STAT signaling pathway and on the structural requirements for STAT activation.

Wang Y et al. (2007) Biophys J "Molecular mechanisms underlying KVS-1-MPS-1 complex assembly."

Sesti F, Wang Y

[Biophys J, 2007]

Formation of heteromeric complexes between voltage-gated K(+) (Kv) channels and accessory (beta) subunits, is a widespread means to generate heterogeneity of K(+) current in the nervous system. Here we investigate the principles that determine the interactions of Caenorhabditis elegans MPS-1--a bifunctional beta-subunit which possesses kinase activity--with Kv channels. MPS-1 belongs to the evolutionarily conserved family of KCNE beta-subunits that modulate the functional properties of a variety of Kv channels and when defective, can cause congenital and acquired disease in Homo sapiens. In Chinese Hamster ovary (CHO) cells, MPS-1 forms stable complexes with different alpha-subunits. The transmembrane domain (TMD) of MPS-1 is necessary and sufficient for MPS-1 complex formation. The hydropathicity of the TMD is an important factor controlling MPS-1 assembly. A highly hydropathic MPS-1 mutant fails to interact with its endogenous channel partners when transgenically expressed in living worms. The hydropathic mechanism does not require specific points of contact between interacting proteins. This may allow MPS-1 to assemble with various Kv channels presumably modifying the electrical properties of each.

Wang Y et al. (2017) Molecules "Calcineurin Antagonizes AMPK to Regulate Lipolysis in Caenorhabditis elegans."

Liang B, Xie C, Wang Y, Diao Z

[Molecules, 2017]

Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase, and the target of immunosuppressive agent tacrolimus (TAC). The dysfunction of calcineurin, or clinical applications of tacrolimus, have been reported to be associated with dyslipidemia. The underlying mechanisms of calcineurin and tacrolimus in lipid metabolism are largely unknown. Here, we showed that mutations of tax-6 and cnb-1, which respectively encode the catalytic subunit and the regulatory subunit of calcineurin, together with tacrolimus treatment, consistently led to decreased fat accumulation and delayed growth in the nematode Caenorhabditis elegans. In contrast, disruption of the AMP-activated protein kinase (AMPK) encoded by aak-1 and aak-2 reversed the above effects in worms. Moreover, calcineurin deficiency and tacrolimus treatment consistently activated the transcriptional expression of the lipolytic gene atgl-1, encoding triglyceride lipase. Furthermore, RNAi knockdown of atgl-1 recovered the decreased fat accumulation in both calcineurin deficient and tacrolimus treated worms. Collectively, our results reveal that immunosuppressive agent tacrolimus and their target calcineurin may antagonize AMPK to regulate ATGL and lipolysis, thereby providing potential therapy for the application of immunosuppressive agents.

Wang Y et al. (2014) G3 (Bethesda) "Identification of suppressors of mbk-2/DYRK by whole-genome sequencing."

Stitzel ML, O'Connell KF, Smith HE, Seydoux G, Wang Y, Wang JT, Rasoloson D

[G3 (Bethesda), 2014]

Screening for suppressor mutations is a powerful method to isolate genes that function in a common pathway or process. Because suppressor mutations often do not have phenotypes on their own, cloning of suppressor loci can be challenging. A method combining whole-genome sequencing (WGS) and single nucleotide polymorphism (SNP) mapping (WGS/SNP mapping) was developed to identify mutations with visible phenotypes in C. elegans. We show here that WGS/SNP mapping is an efficient method to map suppressor mutations without the need for previous phenotypic characterization. Using RNA-mediated interference to test candidate loci identified by WGS/SNP mapping, we identified 10 extragenic and six intragenic suppressors of mbk-2, a DYRK family kinase required for the transition from oocyte to zygote. Remarkably, seven suppressors are mutations in cell-cycle regulators that extend the timing of the oocyte-to-zygote transition.

Wang Y et al. (2011) Neurosci Res "Ethanol interferes with gustatory plasticity in Caenorhabditis elegans."

Wang Y, Feng X, Tang L, Du W, Liu BF

[Neurosci Res, 2011]

Ethanol affects the formation of learning and memory in many species. However, the molecular mechanisms underlying the behavioral effects of ethanol are still poorly understood. In Caenorhabditis elegans, gustatory plasticity is a simple learning paradigm, in which animals after prolonged pre-exposure to a chemo-attractive salt in the absence of food show chemo-aversion to this salt during subsequent chemotaxis test stage. We characterized the effect of ethanol on this simple learning model. Our results showed that ethanol administration interfered with gustatory plasticity during pre-exposure or test stage in well-fed worms. Genetic analysis revealed that one mutant previously implicated involved in acute ethanol responses, slo-1, as well as two mutants with defects in serotonin synthesis, tph-1 and bas-1, failed to exhibit ethanol interference with gustatory plasticity. Furthermore, two metabotropic serotonin receptors, SER-4 and SER-7, were found to be involved in ethanol-mediated gustatory plasticity. In addition, the tph-1 and ser-4 loci were also involved in ethanol's effect on locomotion behavior. These data suggested an essential role of serotonin signaling in modulating acute effects of ethanol.

Wang Y et al. (1997) Nature "Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion."

Wang Y, Hofmann K, Okamoto M, Sudhof TC, Schmitz F

[Nature, 1997]

Rab3 is a neuronal GTP-binding protein that regulates fusion of synaptic vesicles and is essential for long-term potentiation of hippocampal mossy fibre synapses. More than thirty Rab GTP-binding proteins are known to function in diverse membrane transport pathways, although their mechanisms of action are unclear. We have now identified a putative Rab3-effector protein called Rim. Rim is composed of an amino-terminal zinc-finger motif and carboxy-terminal PDZ and C2 domains. It binds only to GTP (but not to GDP)-complexed Rab3, and interacts with no other Rab protein tested. There is enrichment of Rab3 and Rim in neurons, where they have complementary distributions. Rab3 is found only on synaptic vesicles, whereas Rim is localized to presynaptic active zones in conventional synapses, and to presynaptic ribbons in ribbon synapses. Transfection of PC12 cells with the amino-terminal domains of Rim greatly enhances regulated exocytosis in a Rab3-dependent manner. We propose that Rim serves as a Rab3-dependent regulator of synaptic-vesicle fusion by forming a GTP-dependent complex between synaptic plasma membranes and docked synaptic vesicles.

Wang Y et al. (1998) East Coast Worm Meeting "JAK/STAT Signaling Pathway in C. elegans?"

Levy DE, Wang Y

[East Coast Worm Meeting, 1998]

The primary interest of our laboratory is to study JAK/STAT signaling pathway in mice. Though characterized by simplicity and directness in mammalian systems, this pathway is involved in many different regulatory events, such as innate immune responses to viral or bacterial infection, T cell functions, and embryonic development. In Drosophila, a STAT homologue has been identified and shown to be essential for embryonic development. The fact that Dictyostelium discoideum has a STAT-like molecule to regulate its pre-stalk cell differentiation suggests the existence of STAT(s) in a wide variety of organisms. We intend to identify JAK/STAT signaling pathway in C. elegans by cloning worm STAT(s) and use the genetic tools available in nematodes to characterize its role in development.

Wang Y et al. (2024) Environ Pollut "Exposure to 6-PPD quinone enhances glycogen accumulation in Caenorhabditiselegans."

Wang D, Wang Y

[Environ Pollut, 2024]

Glycogen metabolism is an important biological process for organisms. In Caenorhabditis elegans, effect of 6-PPD quinone (6-PPDQ) on glycogen accumulation and underlying mechanism were examined. Exposure to 6-PPDQ (1 and 10 μg/L) increased glycogen accumulation. Meanwhile, exposure to 6-PPDQ (1 and 10 μg/L) increased expression of gsy-1 encoding glycogen synthase and decreased expression of pygl-1 encoding glycogen phosphorylase. In 6-PPDQ exposed animals, glycogen content and glycogen accumulation were inhibited by RNAi of gsy-1 and enhanced by RNAi of pygl-1. RNAi of gsy-1 increased pygl-1 expression, and RNAi of pygl-1 increased gsy-1 expression after 6-PPDQ exposure. In 6-PPDQ exposed nematodes, daf-16 and aak-2 expressions were decreased and glycogen accumulation was suppressed by RNAi of daf-16 and aak-2, suggesting alteration in daf-16 and aak-2 expressions did not mediate glycogen accumulation. Moreover, resistance to 6-PPDQ toxicity on locomotion and brood size was observed in gsy-1(RNAi) animals, and susceptibility to 6-PPDQ toxicity was found in pygl-1(RNAi) animals. Therefore, glycogen accumulation could be enhanced by exposure to 6-PPDQ in nematodes. In addition, alteration in expressions of gsy-1 and pygl-1 governing this enhancement in glycogen accumulation mediated induction of 6-PPDQ toxicity.

Wang Y et al. (2016) ACS Nano "Construction of Nano-Droplet/Adiposome and Artificial Lipid Droplets."

Ma X, Liu P, Zhou XM, Zheng L, Du Y, Wang Y

[ACS Nano, 2016]

The lipid droplet (LD) is a cellular organelle that consists of a neutral lipid core with a monolayer-phospholipid membrane and associated proteins. Recent LD studies demonstrate its importance in metabolic diseases and biofuel development. However, the mechanisms governing its formation and dynamics remain elusive. Therefore, we developed an in vitro system to facilitate the elucidation of these mechanisms. We generated sphere-shaped structures with a neutral lipid core and a monolayer-phospholipid membrane by mechanically mixing neutral lipids and phospholipids followed by a two-step purification. We named the nano-droplet "adiposome". We then recruited LD structure-like/resident proteins to the adiposome, including the bacterial MLDS, C. elegans MDT-28/PLIN-1, or mammalian perilipin-2. In addition, adipose triglyceride lipase (ATGL) and apolipoprotein A1 (apo A-I) were recruited to adiposome. We termed the functional protein-coated adiposomes, Artificial Lipid Droplets (ALDs). Using this experimental system, different proteins can be recruited to build ALDs for some biological goals and potential usage in drug delivery.