V-ATPase V1 Sector Is Required for Corpse Clearance and Neurotransmission in <i>Caenorhabditis elegans</i>

Ernstrom, Glen G.; Weimer, Robby M.; Pawar, Divya R. L.; Watanabe, Shigeki; Hobson, Robert J.; Greenstein, David; Jørgensen, Erik M.

doi:10.1534/genetics.112.139667

Cited by 24 publications

(18 citation statements)

References 74 publications

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“…To investigate the effect of impaired V-ATPase function in neurons, we examined mutants defective in the V-ATPase subunit UNC-32, which is required for synaptic vesicle acidification [25, 26], using the FLP-3::Venus and IDA-1::GFP reporters described above. unc-32 mutants had low neuropeptide levels and high IDA-1::GFP levels at synapses, molecular defects similar to those of vps-50 mutants (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…SpH is a fusion of the synaptic-vesicle protein synaptobrevin with the pH-sensitive GFP reporter pHluorin, and the pHluorin moiety is localized to the vesicular lumen, where it can be used to assay vesicle pH [27, 28]. SpH has been used to study the effects of mutations in the V-ATPase complex on C. elegans GABAergic neurons [25]. vps-50 mutants, like unc-32 mutants, showed increased SpH fluorescence, indicating that vps-50 mutants are defective in vesicle acidification (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior

et al. 2016

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Summary The modification of behavior in response to experience is crucial for animals to adapt to environmental changes. Although factors such as neuropeptides and hormones are known to function in the switch between alternative behavioral states, the mechanisms by which these factors transduce, store, retrieve and integrate environmental signals to regulate behavior are poorly understood. The rate of locomotion of the nematode Caenorhabditis elegans depends on both current and past food availability. Specifically, C. elegans slows its locomotion when it encounters food, and animals in a food-deprived state slow even more than animals in a well-fed state. The slowing responses of well-fed and food-deprived animals in the presence of food represent distinct behavioral states, as they are controlled by different sets of genes, neurotransmitters and neurons. Here we describe an evolutionarily conserved C. elegans protein, VPS-50, that is required for animals to assume the well-fed behavioral state. Both VPS-50 and its murine homolog mVPS50 are expressed in neurons, are associated with synaptic and dense-core vesicles and control vesicle acidification and hence synaptic function, likely through regulation of the assembly of the V-ATPase complex. We propose that dense-core vesicle acidification controlled by the evolutionarily conserved protein VPS-50/mVPS50 affects behavioral state by modulating neuropeptide levels and presynaptic neuronal function in both C. elegans and mammals.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior

et al. 2016

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“…Acidification of lysosomal lumen is important for apoptotic cell degradation. Inactivation of the vacuolar H ATPase 12 (vha-12) gene encoding the V1 B subunit of the lysosomal proton pump vacuolar-type ATPase (V-ATPase), impairs the degradation of apoptotic cells (Ernstrom et al 2012).…”

Section: Acidification Of Phagosomal Lumenmentioning

confidence: 99%

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

Conradt

Xue

2016

Genetics

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Programmed cell death is an integral component of Caenorhabditis elegans development. Genetic and reverse genetic studies in C. elegans have led to the identification of many genes and conserved cell death pathways that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular, cell biological, and biochemical studies have revealed the underlying mechanisms that control these three phases of programmed cell death. In particular, the interplay of transcriptional regulatory cascades and networks involving multiple transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 and, in some cases, the ced-3 gene in cells destined to die. A protein interaction cascade involving EGL-1, CED-9, CED-4, and CED-3 results in the activation of the key cell death protease CED-3, which is tightly controlled by multiple positive and negative regulators. The activation of the CED-3 caspase then initiates the cell disassembly process by cleaving and activating or inactivating crucial CED-3 substrates; leading to activation of multiple cell death execution events, including nuclear DNA fragmentation, mitochondrial elimination, phosphatidylserine externalization, inactivation of survival signals, and clearance of apoptotic cells. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general.KEYWORDS Caenorhabditis elegans; activation phase; execution phase; programmed cell death; specification phase; WormBook

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“…The C. elegans genome encodes 21 V-ATPase subunits (see Figure 1A of the accompanying article in this issue by Ernstrom et al 2012), and we examined their expression and RNA interference characteristics (see http://www. wormbase.org/, Jiang et al 2001, andReinke et al 2000).…”

Section: V-atpase Mutant That Specifically Affects Spermatogenesismentioning

confidence: 99%

“…We examined the microarray data for the 21 V-ATPase subunits encoded by Caenorhabditis elegans and found that there are two B-subunit paralogs with strikingly different patterns of expression (Reinke et al 2000;Jiang et al 2001). While the X chromosome-located vha-12 gene showed somatic expression and the accompanying article in this issue by Ernstrom et al (2012) shows the null phenotype of this gene to be lethal, the second gene encoding a B subunit showed upregulated expression during spermatogenesis. We used positional cloning techniques to show that the previously described spe-5 gene, which is on chromosome I (Machaca and L'Hernault 1997), encodes this spermexpressed B subunit.…”

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confidence: 99%

Developmental Genetics of Secretory Vesicle Acidification DuringCaenorhabditis elegansSpermatogenesis

et al. 2012

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Secretory vesicles are used during spermatogenesis to deliver proteins to the cell surface. In Caenorhabditis elegans, secretory membranous organelles (MO) fuse with the plasma membrane to transform spermatids into fertilization-competent spermatozoa. We show that, like the acrosomal vesicle of mammalian sperm, MOs undergo acidification during development. Treatment of spermatids with the V-ATPase inhibitor bafilomycin blocks both MO acidification and formation of functional spermatozoa. There are several spermatogenesis-defective mutants that cause defects in MO morphogenesis, including spe-5. We determined that spe-5, which is on chromosome I, encodes one of two V-ATPase B paralogous subunits. The spe-5 null mutant is viable but sterile because it forms arrested, multi-nucleate spermatocytes. Immunofluorescence with a SPE-5-specific monoclonal antibody shows that SPE-5 expression begins in spermatocytes and is found in all subsequent stages of spermatogenesis. Most SPE-5 is discarded into the residual body during spermatid budding, but a small amount remains in budded spermatids where it localizes to MOs as a discrete dot. The other V-ATPase B subunit is encoded by vha-12, which is located on the X chromosome. Usually, spe-5 mutants are self-sterile in a wild-type vha-12 background. However, an extrachromosomal transgene containing wild-type vha-12 driven by its own promoter allows spe-5 mutant hermaphrodites to produce progeny, indicating that VHA-12 can at least partially substitute for SPE-5. Others have shown that the X chromosome is transcriptionally silent in the male germline, so expression of the autosomally located spe-5 gene ensures that a V-ATPase B subunit is present during spermatogenesis. V ESICULAR organelles in eukaryotic cells frequently maintain an acidic pH (reviewed by Paroutis et al. 2004) that is created by the vacuolar H+-ATPase (V-ATPase). The V-ATPase is a large (910-kDa) molecular machine that couples ATP hydrolysis to the movement of protons across biological membranes. The V-ATPase has a V 0 -sector that creates the pore-for-proton translocation through the lipid bilayer and a V 1 -sector, located in the cytoplasm, that is the site of ATP hydrolysis. Each V-ATPase holoenzyme is composed of 14 different subunits, some of which are present in multiple copies (reviewed by Toei et al. 2010). In yeast, there is one gene for each V-ATPase subunit, except for the "a" subunit, which is encoded by two genes (reviewed by Kane 2006). The physiological properties of the V-ATPase are in part determined by which of these two "a" subunits it contains (Kawasaki-Nishi et al. 2001). In humans and other animals, the "a" and other V-ATPase subunits are encoded by more than one gene (reviewed by Toei et al. 2010). Subunit diversity presumably allows the V-ATPase to be either customized for a specific function or utilized in a tissuespecific fashion.In this article, we use pH-sensitive vital dyes and specific inhibitors to show that sperm-specific MOs use the V-ATPase to acidify their interior a...

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V-ATPase V1 Sector Is Required for Corpse Clearance and Neurotransmission in Caenorhabditis elegans

Cited by 24 publications

References 74 publications

The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior

The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

Developmental Genetics of Secretory Vesicle Acidification DuringCaenorhabditis elegansSpermatogenesis

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