Vacuolar H<sup>+</sup>-ATPase subunits Voa1 and Voa2 cooperatively regulate secretory vesicle acidification, transmitter uptake, and storage

Saw, Ner Mu Nar; Kang, Soo-Young Ann; Parsaud, Leon; Han, Gayoung A.; Jiang, Tiandan; Grzegorczyk, Krzysztof; Surkont, Michael; Sun‐Wada, Ge‐Hong; Wada, Yoh; Li, Lijun; Sugita, Shuzo

doi:10.1091/mbc.e11-02-0155

Cited by 43 publications

(43 citation statements)

References 74 publications

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“…In our current study, we could show that lysosomes purified from PS1KO cells contained markedly lowered levels of V0a1 subunit, which was associated with impaired vATPase assembly on lysosomes and commensurate reductions of lysosomal proton pumping activity. Using siRNA gene knockdown, we further demonstrated that lysosomal acidification and lysosomal enzyme activation require the vATPase V0a1 subunit, in agreement with other findings that V0a1 subunit is critical for vesicular acidification (Raines et al, 2013; Saw et al, 2011). Notably, V0a1 has a long half-life on lysosomes, requiring substantial duration of siRNA exposure (96hrs) to lower lysosomal levels of the subunit sufficiently to alter acidification, which is 48hrs longer than the interval used in the Coen et al study where a pH change could not be detected upon siRNA treatment (Coen et al, 2012).…”

Section: Discussionsupporting

confidence: 90%

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

et al. 2015

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Summary Presenilin-1 (PS1) deletion or Alzheimer’s Disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in PS1KO cells induces abnormal Ca2+ efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca2+. In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca2+ homeostasis, but correcting lysosomal Ca2+ deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss of function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca2+ homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism.

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Section: Discussionsupporting

confidence: 90%

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

et al. 2015

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“…A recent report demonstrated that V0a1 plays an important role in regulating neurotransmitter uptake, storage, and release by exocytic vesicles in neurosecretory PC12 cells (Saw et al, 2011). Here, we found that cleaved caspase 3 was up-regulated and V0a1 was reduced in the NT-3 h group after CA compared to the HT-3 h group.…”

Section: Discussionsupporting

confidence: 50%

Mild hypothermia attenuates post-resuscitation brain injury through a V-ATPase mechanism in a rat model of cardiac arrest

Zhang

Xie

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Although therapeutic hypothermia is an effective treatment for post-resuscitation brain injury after cardiac arrest (CA), the underlying mechanism remains unclear. Vacuolar H + -ATPase (V-ATPase) plays a key role in cellular adaption to a hypoxic environment. This study sought to evaluate the effect of mild hypothermia on V-ATPase and its involvement in neuroprotection after CA. Male Sprague-Dawley rats were subjected to a 6-min CA, resuscitated successfully, and then assigned to either the normothermia (NT) group or the hypothermia (HT) group. Rats were further divided into 2 subgroups based on the time of euthanasia, either 3 or 24 h after CA (NT-3 h, HT-3 h; NT-24 h, HT-24 h). Mild hypothermia was induced following CA and maintained at 33°C for 2 h. Neurologic deficit scores were used to determine the status of neurological function. Brain specimens were analyzed by TUNEL assay, western blotting, and immunohistochemistry. V-ATPase activity was estimated by subtracting total ATP hydrolysis from the bafilomycin-sensitive activity. Mild hypothermia improved the neurological outcome (HT-24 h: 34.3 ± 16.4 vs NT-24 h: 50.3 ± 17.4) and significantly decreased neurocyte apoptosis 24 h after resuscitation. Mild hypothermia significantly increased V0a1 compared to NT-3 h; V0a1 expression was associated with a decrease in the cleaved caspase 3 expression. These findings suggested that mild hypothermia inhibits CA-induced apoptosis in the hippocampus, which may be associated with reduced V-ATPase impairment. These data provide new insights into the protective effects of hypothermia in vivo.

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“…There are 4 isoforms of the V0a subunit, and each isoform is thought to have a role in the trafficking of the V-ATPase to different organelles in various types of cells as well as in the regulatory uncoupling of V0 and V1 and in membrane fusion [9,10,41,42]. The a1V isoform is involved in acidification of endomembrane organelles, especially in the microglia and other secretory cells of the brain and is prevalent in secretory granules of neurons or other cells in the brain; it has a role in the exocytosis of neurotransmitters in those granules [36,43]. The a2V isoform is found in vesicles in the thymus, decidua, hematopoietic cells, dividing cells, epididymal clear cells [11,34,44,45], and on the plasma membranes of macrophages [18,20].…”

Section: Discussionmentioning

confidence: 99%

Expression and role of a2 vacuolar-ATPase (a2V) in trafficking of human neutrophil granules and exocytosis

Gilman‐Sachs

Tikoo

Akman-Anderson

et al. 2015

Journal of Leukocyte Biology

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Neutrophils kill microorganisms by inducing exocytosis of granules with antibacterial properties. Four isoforms of the "a" subunit of V-ATPase-a1V, a2V, a3V, and a4V-have been identified. a2V is expressed in white blood cells, that is, on the surface of monocytes or activated lymphocytes. Neutrophil associated-a2V was found on membranes of primary (azurophilic) granules and less often on secondary (specific) granules, tertiary (gelatinase granules), and secretory vesicles. However, it was not found on the surface of resting neutrophils. Following stimulation of neutrophils, primary granules containing a2V as well as CD63 translocated to the surface of the cell because of exocytosis. a2V was also found on the cell surface when the neutrophils were incubated in ammonium chloride buffer (pH 7.4) a weak base. The intracellular pH (cytosol) became alkaline within 5 min after stimulation, and the pH increased from 7.2 to 7.8; this pH change correlated with intragranular acidification of the neutrophil granules. Upon translocation and exocytosis, a2V on the membrane of primary granules remained on the cell surface, but myeloperoxidase was secreted. V-ATPase may have a role in the fusion of the granule membrane with the cell surface membrane before exocytosis. These findings suggest that the granule-associated a2V isoform has a role in maintaining a pH gradient within the cell between the cytosol and granules in neutrophils and also in fusion between the surface and the granules before exocytosis. Because a2V is not found on the surface of resting neutrophils, surface a2V may be useful as a biomarker for activated neutrophils.

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Vacuolar H⁺-ATPase subunits Voa1 and Voa2 cooperatively regulate secretory vesicle acidification, transmitter uptake, and storage

Abstract: Voa1 and Voa2 cooperatively regulate the acidification and transmitter uptake/storage of dense-core vesicles, although they might not be as critical for exocytosis as recently proposed.

Cited by 43 publications

References 74 publications

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Mild hypothermia attenuates post-resuscitation brain injury through a V-ATPase mechanism in a rat model of cardiac arrest

Expression and role of a2 vacuolar-ATPase (a2V) in trafficking of human neutrophil granules and exocytosis

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Vacuolar H+-ATPase subunits Voa1 and Voa2 cooperatively regulate secretory vesicle acidification, transmitter uptake, and storage

Abstract: Voa1 and Voa2 cooperatively regulate the acidification and transmitter uptake/storage of dense-core vesicles, although they might not be as critical for exocytosis as recently proposed.

Cited by 43 publications

References 74 publications

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Mild hypothermia attenuates post-resuscitation brain injury through a V-ATPase mechanism in a rat model of cardiac arrest

Expression and role of a2 vacuolar-ATPase (a2V) in trafficking of human neutrophil granules and exocytosis

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Vacuolar H⁺-ATPase subunits Voa1 and Voa2 cooperatively regulate secretory vesicle acidification, transmitter uptake, and storage