Vesicle cholesterol controls exocytotic fusion pore

Rituper, Boštjan; Guček, Alenka; Lisjak, Marjeta; Górska, Urszula; Šakanović, Aleksandra; Bobnar, Saša Trkov; Lasič, Eva; Božić, Mićo; Abbineni, Prabhodh S.; Jorgačevski, Jernej; Kreft, Marko; Verkhratsky, Alexei; Platt, Frances M.; Anderluh, Gregor; Stenovec, Matjaž; Božić, Bojan; Coorssen, Jens R.; Zorec, Robert

doi:10.1016/j.ceca.2021.102503

Cited by 17 publications

(9 citation statements)

References 98 publications

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“…We further demonstrate that rather than favoring reshaping broadly, chol drives fusion pore collapse, that is, smaller fusion pores, consistent with early theory on κ G [44,45,59]. Thus, chol accumulation should favor endocytosis (e.g., viral entry through the plasma membrane) and budding [16,33,34,[44][45][46]60], but disfavor viral escape from the endosome that requires expansion to a wide fusion pore [17,61,62]. However, unlike previous models [16,47,48] that proposed fission would occur because of laterally phase separated domains, our model only assumes that: 1) chol prefers thicker bilayers, and 2) fusion pore necks are thinned according to a straightforward mathematical and mechanical analysis.…”

Section: Introductionsupporting

confidence: 87%

“…In any system, an L o /L d phase separation creates a line tension because of hydrophobic mismatch between the thicker L o and thinner L d . Phase separation, line tension, and curvature are coupled [35,42,[44][45][46] and can result in pore closure [16,33,47,48]; chol is central to each of these elements. The simulations in this work link the geometric thinning of the hydrophobic interior to a driving force for phase separation (the difference in thickness between phases).…”

Section: Introductionmentioning

confidence: 99%

“…This work focuses on chol. A body of literature has demonstrated that chol chemistry and concentration dramatically affect virus-endosome fusion [17, 32], as well as plasma membrane fusion and fission [16, 33]. Understanding chol’s role in mechanics is complicated by disparate observations.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic cholesterol redistribution favors membrane fusion pore constriction

Beaven

Sapp

Sodt

2022

Preprint

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Previous experiments have shown that cholesterol strongly prefers concave leaflets (which have negative curvature and are typically thin), but cholesterol also orders and thickens bilayers (promoting liquid-ordered phases with positive curvature). Our all-atom molecular dynamics simulations resolve this discrepancy for highly curved fusion pores, similar to those found in the nascent fusion and terminal fission steps of endo-/exocytosis. We find that cholesterol is strongly excluded by bilayer thinning in the fusion pore neck, which is caused by the neck's net negative Gaussian (saddle) curvature. Consistent with experiment and our fusion pore simulations, analysis of liquid-disordered planar bilayers indicates that cholesterol prefers overall thicker bilayers, but negative leaflet curvature. The exclusion of cholesterol from the neck because of saddle Gaussian curvature implies that it helps drive fusion pore closure, consistent with literature evidence that membrane reshaping is connected to lateral phase separation.

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Section: Introductionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Dynamic cholesterol redistribution favors membrane fusion pore constriction

Beaven

Sapp

Sodt

2022

Preprint

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“…Customized polarization-controlled TIRF microscope was built and employed to measure content releases from the pore of proteoliposomes with single molecule sensitivity and ∼15 ms temporal resolution ( Figure 3B ) [ 51 ]. Regulation of fusion pore by vesicle cholesterol was also demonstrated in lactotroph with structured illumination microscopy [ 55 ]. The understanding of fusion pore dynamics has been greatly enhanced by advanced light imaging techniques.…”

Section: Vesicle Fusion and Exocytosismentioning

confidence: 99%

Illuminating membrane structural dynamics of fusion and endocytosis with advanced light imaging techniques

Chan

Faragalla

2022

Biochemical Society Transactions

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Visualization of cellular dynamics using fluorescent light microscopy has become a reliable and indispensable source of experimental evidence for biological studies. Over the past two decades, the development of super-resolution microscopy platforms coupled with innovations in protein and molecule labeling led to significant biological findings that were previously unobservable due to the barrier of the diffraction limit. As a result, the ability to image the dynamics of cellular processes is vastly enhanced. These imaging tools are extremely useful in cellular physiology for the study of vesicle fusion and endocytosis. In this review, we will explore the power of stimulated emission depletion (STED) and confocal microscopy in combination with various labeling techniques in real-time observation of the membrane transformation of fusion and endocytosis, as well as their underlying mechanisms. We will review how STED and confocal imaging are used to reveal fusion and endocytic membrane transformation processes in live cells, including hemi-fusion; hemi-fission; hemi-to-full fusion; fusion pore opening, expansion, constriction and closure; shrinking or enlargement of the Ω-shape membrane structure after vesicle fusion; sequential compound fusion; and the sequential endocytic membrane transformation from flat- to O-shape via the intermediate Λ- and Ω-shape transition. We will also discuss how the recent development of imaging techniques would impact future studies in the field.

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“…In such a model, cholesterol is enriched and needs to be eliminated from the LB lumen to adjust surfactant cholesterol levels. Recently, it has also been suggested that increased vesicular cholesterol levels reduces fusion pore expansion and hence could limit secretion [ 79 ].…”

Section: Physiological Role For Ion Channels and Transporters On Lamellar Bodiesmentioning

confidence: 99%

Channels and Transporters of the Pulmonary Lamellar Body in Health and Disease

Dietl

Frick

2021

Cells

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The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X4 receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.

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Vesicle cholesterol controls exocytotic fusion pore

Cited by 17 publications

References 98 publications

Dynamic cholesterol redistribution favors membrane fusion pore constriction

Dynamic cholesterol redistribution favors membrane fusion pore constriction

Illuminating membrane structural dynamics of fusion and endocytosis with advanced light imaging techniques

Channels and Transporters of the Pulmonary Lamellar Body in Health and Disease

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