Interaction of the late endo-lysosomal lipid PI(3,5)P2 with the Vph1 isoform of yeast V-ATPase increases its activity and cellular stress tolerance

Banerjee, Subhrajit; Clapp, Kaitlyn; Tarsio, Maureen; Kane, Patricia M.

doi:10.1074/jbc.ra119.008552

Cited by 40 publications

(53 citation statements)

References 64 publications

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“…This is in keeping with findings from the Kane lab and where they used of dioctanoyl (C8) PI(3,5)P2 in AO assays and found that H + pumping was enhanced by this lipid but not by other C8 lipids. (Banerjee et al, 2019). We used C8-PI(3,5)P2 and found a similar effect (not shown).…”

Section: Proton Influx Is Modulated By Pi(35)p2supporting

confidence: 60%

“…In this study we present data showing that altered PI(3,5)P2 levels proportionately affects V-ATPase activity. Elevating PI(3,5)P2 through the hyperactive fab1 T2250A mutation increased V-ATPase activity, whereas blocking Fab1 activity with Apilimod or through kinase dead fab1 EEE mutation decreased V-ATPase function (Banerjee et al, 2019). PI(3,5)P2 levels not only modulate V-ATPase function, but as our previous studies showed, changes in PI(3,5)P2 affect Ca 2+ transport through activation of the Ca 2+ ATPase Pmc1 (Miner et al, 2020).…”

Section: Discussionmentioning

confidence: 68%

“…Recently, others showed that adding exogenous short chain dioctanoyl (C8) PI(3,5)P2 to purified yeast vacuoles augmented proton pumping (Banerjee et al, 2019). This was due in part to the ability of PI(3,5)P2 to stabilize the V1-Vo, an event was dependent on the interactions between the VO subunit Vph1 and this lipid (Li et al, 2014).…”

Section: Proton Influx Is Modulated By Pi(35)p2mentioning

confidence: 99%

“…PI(3,5)P2 has been shown to regulate the V-ATPase and vacuole acidification through the direct physical interaction with the VO subunit Vph1. This interaction stabilizes the assembly of V1-Vo complex to form the active V-ATPase (Banerjee et al, 2019, Li et al, 2014. In the Golgi, Vph1 is replaced by Stv1 and interacts with the compartment rich lipid PI4P instead of PI(3,5)P2, which is only made on late endosomes and lysosomes (Banerjee and Kane, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Reciprocal regulation of vacuolar calcium transport and V-ATPase activity, and the effects of Phosphatidylinositol 3,5-bisphosphate

Miner

Rivera‐Kohr

Zhang

et al. 2020

Preprint

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StatementHere we show that Ca 2+ and H + transport across the vacuole membrane is reciprocally regulated and that it is linked to the production of Phosphatidylinositol 3,5-bisphoshpate. ABSTRACTYeast vacuoles are acidified by the V-ATPase, a protein complex comprised of the membrane embedded VO complex and the soluble cytoplasmic V1 complex. The assembly of the V1-VO holoenzyme is required for the transfer of H + into the vacuole lumen for acidification. The assembly of the V1-VO holoenzyme is stabilized by the lipid phosphatidylinositol 3,5-bisphospate (PI(3,5)P2) made by the PI3P 5-kinase Fab1/PIKfyve. The absence of PI(3,5)P2 leads to the dissociation of the V1 complex from the membrane. Separately, PI(3,5)P2 has been shown to modulate Ca 2+ transport across the vacuole membrane during fission and fusion. Here we examined whether the regulation of H + and Ca 2+ by PI(3,5)P2 are interdependent. We show that modulating extraluminal Ca 2+ concentrations inhibit V-ATPase activity. As extraluminal CaCl2 levels are raised, the activity of H + pumping is reduced. Conversely, chelating free Ca 2+ with EGTA stimulated vacuole acidification. Not only did Ca 2+ levels affect H + translocation, we also show that blocking V-ATPase activity inhibited Ca 2+ transport into the vacuole lumen. Together, these data illustrate that Ca 2+ transport and V-ATPase regulation are interconnected through the modulation of vacuolar lipid profiles. Abbreviations: AO, acridine orange; DAG, diacylglycerol; FCCP, Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone; PA, phosphatidic acid; PI, phosphatidylinositol; PI3P, phosphatidylinositol 3-phosphate; PI(3,5)P2, phosphatidylinositol 3,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TRP, transient receptor potential; YPD, yeast extract, peptone, dextrose. Miner et al. -Reciprocal regulation of V-ATPase and Ca 2+ transport

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Section: Proton Influx Is Modulated By Pi(35)p2supporting

confidence: 60%

Section: Discussionmentioning

confidence: 68%

Section: Proton Influx Is Modulated By Pi(35)p2mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Reciprocal regulation of vacuolar calcium transport and V-ATPase activity, and the effects of Phosphatidylinositol 3,5-bisphosphate

Miner

Rivera‐Kohr

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Therefore, these data suggested that Vph1NT has the capacity to interact with membranes in response to PI(3,5)P 2 levels, and could bind to the lipid directly or indirectly. PI(3,5)P 2 activation of the V-ATPase was pursued biochemically by assessing activation of V-ATPase activity in isolated vacuolar vesicles by short chain lipids (Banerjee et al, 2019). Short chain PI(3,5)P 2 activated both ATPase and proton pumping activity of wild-type vacuolar vesicles, while short chain PI(4)P and PI(3)P provided little or no activation.…”

Section: Vacuolar V-atpases and Pi(35)pmentioning

confidence: 99%

Regulation of V-ATPase Activity and Organelle pH by Phosphatidylinositol Phosphate Lipids

Banerjee

Kane

2020

Front. Cell Dev. Biol.

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Luminal pH and the distinctive distribution of phosphatidylinositol phosphate (PIP) lipids are central identifying features of organelles in all eukaryotic cells that are also critical for organelle function. V-ATPases are conserved proton pumps that populate and acidify multiple organelles of the secretory and the endocytic pathway. Complete loss of V-ATPase activity causes embryonic lethality in higher animals and conditional lethality in yeast, while partial loss of V-ATPase function is associated with multiple disease states. On the other hand, many cancer cells increase their virulence by upregulating V-ATPase expression and activity. The pH of individual organelles is tightly controlled and essential for function, but the mechanisms for compartment-specific pH regulation are not completely understood. There is substantial evidence indicating that the PIP content of membranes influences organelle pH. We present recent evidence that PIPs interact directly with subunit isoforms of the V-ATPase to dictate localization of V-ATPase subpopulations and participate in their regulation. In yeast cells, which have only one set of organelle-specific V-ATPase subunit isoforms, the Golgi-enriched lipid PI(4)P binds to the cytosolic domain of the Golgi-enriched a-subunit isoform Stv1, and loss of PI(4)P binding results in mislocalization of Stv1-containing V-ATPases from the Golgi to the vacuole/lysosome. In contrast, levels of the vacuole/lysosome-enriched signaling lipid PI(3,5)P 2 affect assembly and activity of V-ATPases containing the Vph1 a-subunit isoform. Mutations in the Vph1 isoform that disrupt the lipid interaction increase sensitivity to stress. These studies have decoded "zip codes" for PIP lipids in the cytosolic N-terminal domain of the a-subunit isoforms of the yeast V-ATPase, and similar interactions between PIP lipids and the V-ATPase subunit isoforms are emerging in higher eukaryotes. In addition to direct effects on the V-ATPase, PIP lipids are also likely to affect organelle pH indirectly, through interactions with other membrane transporters. We discuss direct and indirect effects of PIP lipids on organelle pH, and the functional consequences of the interplay between PIP lipid content and organelle pH.

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The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

Castroflorio

Hoed

Svistunova

et al. 2020

Cell. Mol. Life Sci.

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Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment. Graphic abstract

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Interaction of the late endo-lysosomal lipid PI(3,5)P2 with the Vph1 isoform of yeast V-ATPase increases its activity and cellular stress tolerance

Cited by 40 publications

References 64 publications

Reciprocal regulation of vacuolar calcium transport and V-ATPase activity, and the effects of Phosphatidylinositol 3,5-bisphosphate

Reciprocal regulation of vacuolar calcium transport and V-ATPase activity, and the effects of Phosphatidylinositol 3,5-bisphosphate

Regulation of V-ATPase Activity and Organelle pH by Phosphatidylinositol Phosphate Lipids

The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

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