Fat inclusions strongly alter membrane mechanics

Santinho, Alexandre; Chorlay, Aymeric; Forêt, Lionel; Thiam, Abdou Rachid

doi:10.1016/j.bpj.2021.01.009

Cited by 25 publications

(28 citation statements)

References 53 publications

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“…While studies indicate that LD proteins may interact with TGs contained within the LD interior (Olarte et al, 2020), (Santinho et al, 2021), it is unknown whether smectic lipid phase transitions influence LD protein targeting. Therefore, we imaged the canonical LD protein Erg6 tagged with mNeonGreen (Erg6-mNg) over time in AGR conditions.…”

Section: Resultsmentioning

confidence: 99%

Liquid-crystalline lipid phase transitions in lipid droplets selectively remodel the LD proteome

Rogers

Gui

Kovalenko

et al. 2021

Preprint

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Lipid droplets (LDs) are reservoirs for triglycerides (TGs) and sterol-esters (SEs). How lipids are organized within LDs and influence the LD proteome remains unclear. Using in situ cryo-electron tomography, we show that glucose restriction triggers lipid phase transitions within LDs generating liquid-crystalline lattices inside them. Mechanistically, this requires TG lipolysis, which alters LD neutral lipid composition and promotes SE transition to a liquid-crystalline phase. Fluorescence imaging and proteomics further reveal that LD liquid-crystalline lattices selectively remodel the LD proteome. Some canonical LD proteins including Erg6 re-localize to the ER network, whereas others remain on LDs. Model peptide LiveDrop also redistributes from LDs to the ER, suggesting liquid-crystalline-phases influence ER-LD inter-organelle transport. Proteomics also indicates glucose restriction elevates peroxisome lipid oxidation, suggesting TG mobilization provides fatty acids for cellular energetics. This suggests glucose restriction drives TG mobilization, which alters the phase properties of LD lipids and selectively remodels the LD proteome.

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Section: Resultsmentioning

confidence: 99%

Liquid-crystalline lipid phase transitions in lipid droplets selectively remodel the LD proteome

Rogers

Gui

Kovalenko

et al. 2021

Preprint

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“…Finally, we note that TG itself can significantly alter the membrane properties. It was recently shown experimentally 47 and computationally 12 that TG reduces bending modulus of a bilayer membrane. The other neutral lipid, diacylglycerol, can also reduce membrane rigidity.…”

Section: Discussionmentioning

confidence: 96%

Key Factors Governing Initial Stages of Lipid Droplet Formation

Kim

Farese

et al. 2021

Preprint

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Lipid droplets (LDs) are neutral lipid storage organelles surrounded by a phospholipid (PL) monolayer. LD biogenesis from the endoplasmic reticulum (ER) is driven by phase separation of neutral lipids, overcoming surface tension and membrane deformation. However, the core biophysics of the initial steps of LD formation remain relatively poorly understood. Here, we use a tunable, phenomenological coarse-grained (CG) model to study triacylglycerol (TG) nucleation in a bilayer membrane. We show that PL rigidity has a strong influence on TG lensing and membrane remodeling: When membrane rigidity increases, TG clusters remain more planar with high anisotropy but a minor degree of phase nucleation. This finding is confirmed by free energy sampling simulations that calculate the potential of mean force (PMF) as a function of the degree of nucleation and anisotropy. We also show that asymmetric tension, controlled by the number of PLs on each membrane leaflet, determines the budding direction. A TG lens buds in the direction of the monolayer containing excess PLs to allow for better PL coverage of TG, consistent with reported experiments. Finally, two governing mechanisms of the LD growth, Ostwald ripening and merging, are observed. Taken together, this study characterizes the interplay between two thermodynamic quantities during the initial LD phases, the TG bulk free energy and membrane remodeling energy.

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“…When the surface tension of DEVs is increased, TG molecules partition from the droplet to the bilayer. 67,68 We used this strategy to increase TG levels in the bilayer and determine if this would favor D2 recruitment to the bilayer, as seen with GERVs. After D2 bound to the droplet of DEVs, we increased the bilayer tension by adding water to the bulk medium (Figure 6B) to provoke the system's swelling and the delivery of TG to the bilayer.…”

Section: D2 Binds To Bilayer Membranes Physically Connected To Tg Dropletsmentioning

confidence: 99%

Hepatitis C virus core protein uses triacylglycerols to fold onto the endoplasmic reticulum membrane

Ajjaji

M’Barek

Boson

et al. 2021

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Lipid droplets (LDs) are involved in viral infections, but exactly how remains unclear.Here, we study the hepatitis C virus (HCV) whose core capsid protein binds to LDs but is also involved in the assembly of virions at the endoplasmic reticulum (ER) bilayer. We found that the amphipathic helix-containing domain of core, D2, senses triglycerides (TGs) rather than LDs per se. In the absence of LDs, D2 can bind to the ER membrane but only if TG molecules are present in the bilayer. Accordingly, the pharmacological inhibition of the diacylglycerol O-acyltransferase enzymes, mediating TG synthesis in the ER, inhibits D2 association with the bilayer. We found that TG molecules enable D2 to fold into alpha helices. Sequence analysis reveals that D2 resembles the apoE lipid-binding region. Our data support that TG in LDs promotes the folding of core, which subsequently relocalizes to contiguous ER regions. During this motion, core may carry TG molecules to these regions where HCV lipoviroparticles likely assemble. Consistent with this model, the inhibition of Arf1/ COPI, which decreases LD surface accessibility to proteins and ER-LD material exchange, severely impedes the assembly of virions. Altogether, our data uncover a critical function of TG in the folding of core and HCV replication and reveals, more broadly, how TG accumulation in the ER may provoke the binding of soluble amphipathic helix-containing proteins to the ER bilayer.

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Fat inclusions strongly alter membrane mechanics

Cited by 25 publications

References 53 publications

Liquid-crystalline lipid phase transitions in lipid droplets selectively remodel the LD proteome

Liquid-crystalline lipid phase transitions in lipid droplets selectively remodel the LD proteome

Key Factors Governing Initial Stages of Lipid Droplet Formation

Hepatitis C virus core protein uses triacylglycerols to fold onto the endoplasmic reticulum membrane

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