Role of curvature and phase transition in lipid sorting and fission of membrane tubules

Roux, Aurélien; Cuvelier, Damien; Nassoy, Pierre; Prost, Jacques; Bassereau, Patricia; Goud, Bruno

doi:10.1038/sj.emboj.7600631

Cited by 446 publications

(417 citation statements)

References 36 publications

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“…Mitochondrial fission requires local bending of lipid bilayers, which appears to be disfavoured in ordered membrane microdomains. 32 These in vitro observations prompted us to test whether increasing cholesterol levels in mitochondria would also alter Bax activation in vivo and consequently retard cell death. We used U18666A as a tool to increase mitochondrial cholesterol levels and to test the validity of our in vitro results in a more physiological system.…”

Section: Discussionmentioning

confidence: 99%

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

2007

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Activation of Bax or Bak is essential for the completion of many apoptotic programmes. Under cytotoxic conditions, these proteins undergo a series of conformational rearrangements that end up with their oligomerization. We found that unlike inactive monomeric Bax, active oligomerized Bax is partially resistant to trypsin digestion, providing a convenient read out to monitor Bax activation. Using this assay, we studied how the lipid composition of membranes affects tBid-induced Bax activation in vitro with pure liposomes. We report that Bax activation is inhibited by cholesterol and by decreases in membrane fluidity. This observation was further tested in vivo using the drug U18666A, which we found increases mitochondrial cholesterol levels. When incubated with tBid, mitochondria isolated from U18666A-treated cells showed a delay in the release of Smac/Diablo and Cytochrome c, as well as in Bax oligomerization. Moreover, pre-incubation with U18666A partially protected cells from stressinduced apoptosis. As many tumours display high mitochondrial cholesterol content, inefficient Bax oligomerization might contribute to their resistance to apoptosis-inducing agents. Among the stimuli that lead to apoptosis, a series of stress conditions trigger the permeabilization of the mitochondrial outer membrane (MOM) and the release of pro-apoptotic factors that will activate caspases in the cytosol. This so-called intrinsic apoptotic pathway is tightly regulated by proteins of the Bcl-2 family, among which the pro-apoptotic members Bax and Bak are essential. They seem to be the central players whose activation results in MOM permeabilization.Under resting conditions, whereas Bak essentially resides in the MOMs, Bax is found in loose association with membranes (mainly the MOMs) or as a soluble protein in the cytosol. Following many cytotoxic signals, Bax and Bak undergo a series of conformational rearrangements. 1 Bax translocates to mitochondria and inserts into the MOMs in a form that cannot be detached by alkali treatment. Bax and Bak then uncover N-terminal epitopes and oligomerize. Oligomerization, shown by size exclusion chromatography, 2 crosslinking experiments 3,4 and native gel electrophoresis, 5 appears as the critical step resulting in MOM permeabilization. However, despite many efforts, it remains unclear how each of these conformational rearrangements is regulated, and how Bax/Bak oligomerization leads to the release of mitochondrial apoptogenic factors. Both processes are undoubtedly regulated by other members of the Bcl-2 family, 6,7 but the participation of many unrelated proteins was also proposed. 8 While a BH3-only protein appears to be sufficient for Bax to oligomerize in synthetic liposomes, 9,10 additional proteins could be required for its activation in isolated mitochondria. 11 These might directly interact with Bax, and/or modify the membrane properties to allow its oligomerization. Interaction with mitochondrial lipids is indeed an important parameter to consider as the final conformational rearrange...

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Section: Discussionmentioning

confidence: 99%

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

2007

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“…• Cells are not simple spheres, and local differences in membrane curvature can have profound effects on lipid sorting 71 .…”

Section: Box 3 Extrapolating From Model Membranes To the Plasma Membranementioning

confidence: 99%

Lipid rafts: contentious only from simplistic standpoints

Hancock

2006

Nat Rev Mol Cell Biol

742

713

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The hypothesis that lipid rafts exist in plasma membranes and have crucial biological functions remains controversial. The lateral heterogeneity of proteins in the plasma membrane is undisputed, but the contribution of cholesterol-dependent lipid assemblies to this complex, non-random organization promotes vigorous debate. In the light of recent studies with model membranes, computational modelling and innovative cell biology, I propose an updated model of lipid rafts that readily accommodates diverse views on plasma-membrane micro-organization.A widely accepted hypothesis in contemporary cell biology is that freely diffusing, stable, lateral assemblies of sphingolipids and cholesterol, which are termed lipid rafts 1-3 , constitute an important organizing principle for the plasma membrane. The basic concept is that lipid rafts can facilitate selective protein-protein interactions by selectively excluding or including proteins. This lipid-based sorting mechanism has been widely implicated in the assembly of transient signalling platforms and more permanent structures such as the immunological synapse, as well as in the sorting of proteins for entry into specific exocytic and endocytic trafficking pathways [1][2][3] . Despite the undoubted theoretical utility of lipid rafts to many cell biological processes, the basic hypothesis that stable lipid rafts exist at all in biological membranes is under intense scrutiny 4,5 . This is partly because lipid rafts, if they exist in resting cell membranes, are too small to be resolved by fluorescent microscopy and have no defined ultrastructure; therefore, proving their existence is problematic. This article will consider the biophysical properties of model membranes that underpin the lipid raft hypothesis, and the limitations of the biochemical approaches that have been used to study rafts in biological membranes that largely account for the current debate on the hypothesis mentioned above. After examining the challenges that are involved in correlating observations, which have been made in model and cellular membranes, I focus on synthesizing recent data on the size of lipid domains in model membranes with observations that have been obtained by imaging intact plasma membranes. These imaging approaches include single particle tracking (SPT), single fluorophore video tracking (SFVT), fluorescence resonance energy transfer (FRET), homo-FRET and electron microscopy (EM). On the one hand, these studies challenge the simplistic null hypothesis that lipid-based assemblies, such as lipid rafts, do not exist in biological membranes. On the other hand, it is timely to reconsider the raft hypothesis in the light of these new data because the consensus model that emerges is more complex than a simplistic notion of stable, freely diffusing lipid rafts. Some intriguing new questions aboutCompeting interests statement The author declares no competing financial interests. DATABASES

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“…Alternatively, FisB could induce lateral segregation of CL (de Kruijff and Cullis 1980), with the resulting line tension and/or the discontinuity in elastic properties between the CL-rich and CL-poor phases leading spontaneously to fission. Such fission occurs at domain boundaries between cholesterol-rich and cholesterol-poor tubules under certain conditions (Allain et al 2004;Roux et al 2005). Finally, FisB might act through a mechanism reminiscent of viral fusion proteins.…”

Section: How Might Fisb Mediate Membrane Scission?mentioning

confidence: 99%

FisB mediates membrane fission during sporulation in Bacillus subtilis

et al. 2013

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How bacteria catalyze membrane fission during growth and differentiation is an outstanding question in prokaryotic cell biology. Here, we describe a protein (FisB, for fission protein B) that mediates membrane fission during the morphological process of spore formation in Bacillus subtilis. Sporulating cells divide asymmetrically, generating a large mother cell and smaller forespore. After division, the mother cell membranes migrate around the forespore in a phagocytic-like process called engulfment. Membrane fission releases the forespore into the mother cell cytoplasm. Cells lacking FisB are severely and specifically impaired in the fission reaction. Moreover, GFP-FisB forms dynamic foci that become immobilized at the site of fission. Purified FisB catalyzes lipid mixing in vitro and is only required in one of the fusing membranes, suggesting that FisB-lipid interactions drive membrane remodeling. Consistent with this idea, the extracytoplasmic domain of FisB binds with remarkable specificity to cardiolipin, a lipid enriched in the engulfing membranes and regions of negative curvature. We propose that membrane topology at the final stage of engulfment and FisB-cardiolipin interactions ensure that the mother cell membranes are severed at the right time and place. The unique properties of FisB set it apart from the known fission machineries in eukaryotes, suggesting that it represents a new class of fission proteins.

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Role of curvature and phase transition in lipid sorting and fission of membrane tubules

Cited by 446 publications

References 36 publications

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

Lipid rafts: contentious only from simplistic standpoints

FisB mediates membrane fission during sporulation in Bacillus subtilis

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