Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor

Malia, PC; Numrich, Johannes; Nishimura, Taki; Montoro, Ayelén González; Stefan, Christopher J.; Ungermann, Christian

doi:10.1073/pnas.1722517115

Cited by 27 publications

(30 citation statements)

References 45 publications

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“…Ivy1 is an effector of Ypt7, a small GTPase involved in vacuolar fusion, localizes to vacuoles and is a regulator of vacuolar membrane homeostasis. Ivy1 has also been shown to bind and inhibit the Fab1 complex, which generates phosphatidylinositol 3,5-bisphosphate [PI(3,5)P 2 ], which, in turn, regulates vacuolar dynamics (Malia et al, 2018). A key structural feature of Ivy1 is its inverse BAR (I-BAR) domain (Itoh et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Ivy1 is a negative regulator of Gtr-dependent TORC1 activation

Varlakhanova

Tornabene

Ford

2018

Journal of Cell Science

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The highly conserved TORC1 complex controls cell growth in response to nutrients, especially amino acids. The EGO complex activates TORC1 in response to glutamine and leucine. Here, we demonstrate that the I-BAR domain-containing protein Ivy1 colocalizes with Gtr1 and Gtr2, a heterodimer of small GTPases that are part of the EGO complex. Ivy1 is a negative regulator of Gtr-induced TORC1 activation, and is contained within puncta associated with the vacuolar membrane in cells grown in nutrient-rich medium or after brief nitrogen starvation. Addition of glutamine to nitrogen-starved cells leads to dissipation of Ivy1 puncta and redistribution of Ivy1 throughout the vacuolar membrane. Continued stimulation with glutamine results in concentration of Ivy1 within vacuolar membrane invaginations and its spatial separation from the EGO complex components Gtr1 and Gtr2. Disruption of vacuolar membrane invagination is associated with persistent mislocalization of Ivy1 across the vacuolar membrane and inhibition of TORC1 activity. Together, our findings illustrate a novel negative-feedback pathway that is exerted by Ivy1 on Gtr-dependent TORC1 signaling and provide insight into a potential molecular mechanism underlying TORC1 activation by vacuolar membrane remodeling.

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Section: Introductionmentioning

confidence: 99%

Ivy1 is a negative regulator of Gtr-dependent TORC1 activation

Varlakhanova

Tornabene

Ford

2018

Journal of Cell Science

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“…Recently, this mechanism was also shown to promote fission by disrupting the interaction between the I-BAR protein Ivy1 and Ypt7 to activate Fab1 and synthesize PI-3,5-P2 (Malia et al, 2018). But it remains unclear if lumenal volume loss and subsequent changes in lipid bilayer packing or lateral tension induced 5 by hypertonic stress is necessary for Ivy to activate Fab1.…”

Section: Rab Inactivation Alone Can Drive Vacuole Fissionmentioning

confidence: 99%

“…From these studies, it was revealed that Vac14 is required for activation of Fab1 in response to a decrease in organelle volume induced by hypertonic stress (Bonangelino et al, 2002). Recently, Ivy1, an inhibitor of Fab1, inverted BAR (I-BAR) protein and effector of the RabGTPase Ypt7 was also implicated in this response (Malia et al, 2018): When Ypt7 is inactivated…”

Section: Introductionmentioning

confidence: 99%

“…Or is it needed to induce changes in membrane properties to inactivate Ivy1 (see Malia et al, 2018)? Also, acetate was shown to stimulate vacuole fission in vitro (Michaillat et al, 2012).…”

mentioning

confidence: 99%

“…Subsequent release of Ivy1 would stimulate Fab1 (Malia et al, 2018). This working model also explains how inactivation of Ypt7 alone triggers fission: By bypassing Vac14 and Vps39, Rab-GAP-mediated inactivation of Ypt7 would simply release Ivy1 to stimulate Fab1 and drive fission.…”

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confidence: 99%

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Acetate and hypertonic stress stimulate organelle membrane fission using distinct phosphatidylinositol signals

Patel¹,

Cl²

2018

Preprint

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Running Title Vacuole morphology control by Rab and PI signalingFor social media (@drbrettphd) Organelle morphology reflects a balance between fission and fusion. Using the yeast vacuole as a model, Patel and Brett use a new in vitro fission assay to further resolve the molecular circuitry that underlies these opposing processes. KeywordsMembrane fission, membrane fusion, organelle morphology, yeast vacuole, phosphatidylinositol . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/398685 doi: bioRxiv preprint first posted online Aug. 23, 2018;Patel & Brett, page 2 ABSTRACT Organelle morphology reflects an equilibrium between membrane fusion and fission that determines size, shape and copy number. By studying the yeast vacuole as a model, the conserved molecular mechanisms responsible for organelle fusion have been revealed. 5However, a detailed understanding of vacuole fission and how these opposing processes respond to the cell cycle, osmoregulation or metabolism to change morphology remain elusive.Thus, herein we describe a new fluorometric assay to measure vacuole fission in vitro. For proof-of-concept, we use this assay to confirm that acetate, a key intermediary metabolite, triggers vacuole fission in vitro and show that it also blocks homotypic vacuole fusion. The basis 10 of this effect is distinct from hypertonic stress, a known trigger of fission and inhibitor of fusion that inactivates the Rab-GTPase Ypt7: Treatment with the phosphatidylinositol-kinase inhibitor wortmannin or the catalytic domain of the Rab-GAP (GTPase Activating Protein) Gyp1 reveal that fission can be triggered by Ypt7 inactivation alone in absence of hypertonic stress, placing it upstream of PI-3,5-P2 synthesis and osmosis required for membrane scission. Whereas acetate 15 seems to block PI-4-kinase to possibly increase the pool of PI on vacuole membranes needed to synthesize sufficient PI-3,5-P2 for fission. Thus, we speculate that both PI-4-P and PI-3-P arms of PI-P signaling drive changes in membrane fission and fusion responsible altering vacuole morphology in response to cellular metabolism or osmoregulation.

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Low‐level lysosomal membrane permeabilization for limited release and sublethal functions of cathepsin proteases in the cytosol and nucleus

Reinheckel

Tholen

2022

FEBS Open Bio

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For a long time, lysosomes were purely seen as organelles in charge of garbage disposal within the cell. They destroy any cargo delivered into their lumen with a plethora of highly potent hydrolytic enzymes, including various proteases. In case of damage to their limiting membranes, the lysosomes release their soluble content with detrimental outcomes for the cell. In recent years, however, this view of the lysosome changed towards acknowledging it as a platform for integration of manifold intracellular and extracellular signals. Even impaired lysosomal membrane integrity is no longer considered to be a one‐way street to cell death. Increasing evidence suggests that lysosomal enzymes, mainly cathepsin proteases, can be released in a spatially and temporarily restricted manner that is compatible with cellular survival. This way, cathepsins can act in the cytosol and the nucleus, where they affect important cellular processes such as cell division. Here, we review this evidence and discuss the routes and molecular mechanisms by which the cathepsins may reach their unusual destination.

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Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor

Cited by 27 publications

References 45 publications

Ivy1 is a negative regulator of Gtr-dependent TORC1 activation

Ivy1 is a negative regulator of Gtr-dependent TORC1 activation

Acetate and hypertonic stress stimulate organelle membrane fission using distinct phosphatidylinositol signals

Low‐level lysosomal membrane permeabilization for limited release and sublethal functions of cathepsin proteases in the cytosol and nucleus

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