Cytosolic pH is a second messenger for glucose and regulates the PKA pathway through V-ATPase

Dechant, Reinhard; Binda, Matteo; Lee, Sung Sik; Pelet, Serge; Winderickx, Joris; Peter, Matthias

doi:10.1038/emboj.2010.138

Cited by 273 publications

(341 citation statements)

References 82 publications

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“…The mechanism of V-ATPase regulation by reversible dissociation was first described in yeast (9) and insects (11) but has since been found to be a general mechanism for enzyme regulation in higher eukaryotes (32)(33)(34). Although this unique mode of regulation is well documented, the molecular mechanism remains poorly understood.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, a number of environmental signals have been linked to enzyme dissociation, mainly related to metabolism and specifically glycolysis (10). Changes in enzyme association have been linked to phosphorylation (47), extracellular conditions (48), pH changes (34,48), and subcellular localization (33,49). Further complicating the understanding of this mechanism are the number of cellular binding partners for subunits likely to be involved in enzyme regulation.…”

Section: Discussionmentioning

confidence: 99%

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Subunit Interactions at the V1-Vo Interface in Yeast Vacuolar ATPase

Oot

Wilkens

2012

Journal of Biological Chemistry

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Background:The activity of the proton pumping vacuolar ATPase is regulated by reversible enzyme dissociation. Results: The ATPase and proton channel domains are held together by several intermediate affinity interactions. Conclusion: Intermediate affinity subunit-subunit interactions may play an important role in reversible enzyme dissociation. Significance: Targeting subunit-subunit interactions may be a means of modulating aberrant V-ATPase activity involved in human disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Subunit Interactions at the V1-Vo Interface in Yeast Vacuolar ATPase

Oot

Wilkens

2012

Journal of Biological Chemistry

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“…Control of one by the other, as suggested by our results, may reflect unanticipated inter-ATPase communication. Indeed, V-ATPase function has been linked to Wnt (40) and Notch (41) signaling and to nutrient-responsive signaling through pH control (42). Nutrient-responsive signaling has also been linked to mitochondrial DNA damage (43).…”

Section: Discussionmentioning

confidence: 99%

Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency, and drug sensitivity in trypanosomes

Baker

Hamilton

Wilkes

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Kinetoplastid parasites cause lethal diseases in humans and animals. The kinetoplast itself contains the mitochondrial genome, comprising a huge, complex DNA network that is also an important drug target. Isometamidium, for example, is a key veterinary drug that accumulates in the kinetoplast in African trypanosomes. Kinetoplast independence and isometamidium resistance are observed where certain mutations in the F 1 -γ-subunit of the two-sector F 1 F o -ATP synthase allow for F o -independent generation of a mitochondrial membrane potential. To further explore kinetoplast biology and drug resistance, we screened a genome-scale RNA interference library in African trypanosomes for isometamidium resistance mechanisms. Our screen identified 14 V-ATPase subunits and all 4 adaptin-3 subunits, implicating acidic compartment defects in resistance; V-ATPase acidifies lysosomes and related organelles, whereas adaptin-3 is responsible for trafficking among these organelles. Independent strains with depleted V-ATPase or adaptin-3 subunits were isometamidium resistant, and chemical inhibition of the V-ATPase phenocopied this effect. While drug accumulation in the kinetoplast continued after V-ATPase subunit depletion, acriflavine-induced kinetoplast loss was specifically tolerated in these cells and in cells depleted for adaptin-3 or endoplasmic reticulum membrane complex subunits, also identified in our screen. Consistent with kinetoplast dispensability, V-ATPase defective cells were oligomycin resistant, suggesting ATP synthase uncoupling and bypass of the normal F o -A6-subunit requirement; this subunit is the only kinetoplast-encoded product ultimately required for viability in bloodstream-form trypanosomes. Thus, we describe 30 genes and 3 protein complexes associated with kinetoplast-dependent growth. Mutations affecting these genes could explain natural cases of dyskinetoplasty and multidrug resistance. Our results also reveal potentially conserved communication between the compartmentalized two-sector rotary ATPases.brucei | mitochondrion | nagana | petite | samorin

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“…Instead, it may be that the vph1⌬ mutation also compromises glucose signaling to Pma1. Significantly, recent work has suggested that the V-ATPase may play a role in mediating certain glucose signals (29); it is possible that the pathways that activate Pma1 in response to glucose are affected by the vph1⌬ mutation. Cytosolic acidification without Pma1 mislocalization was also observed after a brief treatment with the V-ATPase inhibitor concanamycin A (12), also suggesting a second mechanism for down-regulation of Pma1 activity.…”

Section: Discussionmentioning

confidence: 99%

Consequences of Loss of Vph1 Protein-containing Vacuolar ATPases (V-ATPases) for Overall Cellular pH Homeostasis

Tarsio

Zheng

Smardon

et al. 2011

Journal of Biological Chemistry

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In yeast cells, subunit a of the vacuolar proton pump (VATPase) is encoded by two organelle-specific isoforms, VPH1 and STV1. V-ATPases containing Vph1 and Stv1 localize predominantly to the vacuole and the Golgi apparatus/endosomes, respectively. Ratiometric measurements of vacuolar pH confirm that loss of STV1 has little effect on vacuolar pH. Loss of VPH1 results in vacuolar alkalinization that is even more rapid and pronounced than in vma mutants, which lack all V-ATPase activity. Cytosolic pH responses to glucose addition in the vph1⌬ mutant are similar to those in vma mutants. The extended cytosolic acidification in these mutants arises from reduced activity of the plasma membrane proton pump, Pma1p. Pma1p is mislocalized in vma mutants but remains at the plasma membrane in both vph1⌬ and stv1⌬ mutants, suggesting multiple mechanisms for limiting Pma1 activity when organelle acidification is compromised. pH measurements in early prevacuolar compartments via a pHluorin fusion to the Golgi protein Gef1 demonstrate that pH responses of these compartments parallel cytosolic pH changes. Surprisingly, these compartments remain acidic even in the absence of V-ATPase function, possibly as a result of cytosolic acidification. These results emphasize that loss of a single subunit isoform may have effects far beyond the organelle where it resides.Vacuolar proton-translocating ATPases (V-ATPases) 3 acidify multiple organelles, including mammalian lysosomes, plant and fungal vacuoles, the Golgi apparatus, endosomes, and regulated secretory granules. Through their effects on organelle acidification, V-ATPases impact numerous cellular processes including protein sorting, macromolecular degradation, cytosolic pH and ion homeostasis, and nutrient storage and mobilization (1, 2). Consistent with these diverse roles, complete loss of V-ATPase function is lethal in most organisms. Fungi, however, can tolerate a complete loss of V-ATPase function, and Saccharomyces cerevisiae has emerged as a major model system for mechanistic studies of V-ATPases (3). Yeast mutants lacking V-ATPase activity (vma mutants) show a well defined set of Vma Ϫ growth phenotypes, including sensitivity to high extracellular pH, high Ca 2ϩ concentrations, and heavy metals (4).V-ATPases are highly conserved both at the level of individual subunit sequences and at an overall structural level. A complex of peripheral membrane subunits containing the sites of ATP hydrolysis, V 1 , is attached to an integral membrane complex, V o , containing the proton pore. In higher eukaryotes, many of the subunits are present as multiple isoforms, encoded as multiple genes and/or splice variants (5). These subunit isoforms exhibit tissue-specific expression and/or organelle-specific localization, and in some cases, impart different biochemical characteristics on V-ATPases, possibly tuning their activity to the requirements of different locales (2). Subunit a of the V o sector is present as multiple isoforms in many organisms. Humans have four different subunit a genes (...

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Cytosolic pH is a second messenger for glucose and regulates the PKA pathway through V-ATPase

Cited by 273 publications

References 82 publications

Subunit Interactions at the V1-Vo Interface in Yeast Vacuolar ATPase

Subunit Interactions at the V1-Vo Interface in Yeast Vacuolar ATPase

Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency, and drug sensitivity in trypanosomes

Consequences of Loss of Vph1 Protein-containing Vacuolar ATPases (V-ATPases) for Overall Cellular pH Homeostasis

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