Sterols are moved between cellular membranes by nonvesicular pathways whose functions are poorly understood. In yeast, one such pathway transfers sterols from the plasma membrane (PM) to the ...endoplasmic reticulum (ER). We show that this transport requires oxysterol-binding protein (OSBP)-related proteins (ORPs), which are a large family of conserved lipid-binding proteins. We demonstrate that a representative member of this family, Osh4p/Kes1p, specifically facilitates the nonvesicular transfer of cholesterol and ergosterol between membranes in vitro. In addition, Osh4p transfers sterols more rapidly between membranes containing phosphoinositides (PIPs), suggesting that PIPs regulate sterol transport by ORPs. We confirmed this by showing that PM to ER sterol transport slows dramatically in mutants with conditional defects in PIP biosynthesis. Our findings argue that ORPs move sterols among cellular compartments and that sterol transport and intracellular distribution are regulated by PIPs.
Fouling caused by soluble microbial products (SMP) in membrane bioreactors (MBRs) is a critical problem, and a general understanding on SMP fouling behaviors has not been well established due to the ...complex interactions between SMP and membranes. In the present work, alginate solution was chosen as a model SMP foulant, and the effects of solution chemistry on the interaction energy between alginate and polymeric membranes were assessed by the extended Derjaguin–Landau–Verwey–Overbeek (XDLVO) theory. The results showed that the pH and ionic strength levels of the solution had significant effects on the solution properties and the interaction energy between alginate and membranes. The free energy of cohesion of alginate was maximal at pH 6.5 and ionic strength 10mM. Either increase or decrease of pH could lessen its cohesion free energy. Increase of ionic strength reduced the free energy of cohesion and made alginate solution more unstable and hydrophobic. Energy barrier between alginate and membranes was reduced under higher ionic strength and acidic condition, which was supported by fouling filtration experiments. It was also found that after the formation of initial fouling layer onto membranes, membrane fouling was controlled by cohesion free energy between approaching alginate and alginate-modified surfaces. This study demonstrated that XDLVO-model is sufficient to assess short-range membrane–foulant interactions and to predict SMP fouling in MBRs.
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•We examine the interaction energy between membrane and alginate by the XDLVO theory.•High ionic strength and strong acidic condition can reduce interaction energy.•Cohesion free energy between alginate and virgin membrane governs initial fouling.•Interactions of foulant and foulant-modified surface dominate after initial fouling.•XDLVO-model can well characterize and predict biofouling behaviors.
Degradation of endoplasmic reticulum (ER) by selective autophagy (ER‐phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal ...sequestration and lysosomal degradation. Here, we show that oligomerization of ER‐phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon‐homology domain is required for membrane fragmentation in vitro and ER‐phagy in vivo. Under ER‐stress conditions, activated CAMK2B phosphorylates the reticulon‐homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER‐phagy. Unexpectedly, FAM134B G216R, a variant derived from a type II hereditary sensory and autonomic neuropathy (HSAN) patient, exhibits gain‐of‐function defects, such as hyperactive self‐association and membrane scission, which results in excessive ER‐phagy and sensory neuron death. Therefore, this study reveals a mechanism of ER membrane fragmentation in ER‐phagy, along with a signaling pathway in regulating ER turnover, and suggests a potential implication of excessive selective autophagy in human diseases.
Synopsis
How endoplasmic reticulum (ER) membranes are fragmented for subsequent autophagic degradation (ER‐phagy) is ill‐defined. CAMK2B‐dependent phosphorylation of ER‐phagy receptor FAM134B promotes its oligomerization and membrane scission activity, a process deregulated in sensory neuropathy.
ER‐phagy receptor FAM134B oligomerizes through its reticulon‐homology domain (RHD).
FAM134B oligomerization is required for ER membrane scission prior to autophagosomal engulfment.
ER stress triggers the activation of CAMK2B, which phosphorylates FAM134B to enhance ER membrane fragmentation and ER‐phagy.
An HSAN type‐II patient‐derived variant, FAM134B‐G216R, forms higher‐order oligomers and induces massive ER‐phagy, which leads to sensory neuron death.
CAMK2B‐dependent phosphorylation of autophagy receptor FAM134B promotes its oligomerization and membrane‐scission activity, a process deregulated in sensory neuropathy.
From the moment of cotranslational insertion into the lipid bilayer of the endoplasmic reticulum (ER), newly synthesized integral membrane proteins are subject to a complex series of sorting, ...trafficking, quality control, and quality maintenance systems. Many of these processes are intimately controlled by ubiquitination, a posttranslational modification that directs trafficking decisions related to both the biosynthetic delivery of proteins to the plasma membrane (PM) via the secretory pathway and the removal of proteins from the PM via the endocytic pathway. Ubiquitin modification of integral membrane proteins (or "cargoes") generally acts as a sorting signal, which is recognized, captured, and delivered to a specific cellular destination via specialized trafficking events. By affecting the quality, quantity, and localization of integral membrane proteins in the cell, defects in these processes contribute to human diseases, including cystic fibrosis, circulatory diseases, and various neuropathies. This review summarizes our current understanding of how ubiquitin modification influences cargo trafficking, with a special emphasis on mechanisms of quality control and quality maintenance in the secretory and endocytic pathways.
Stimuli‐Responsive Smart Membranes
In article number 2211983, Yanxin Wang, Jianguo Tang, Linjun Huang, Jun Chen, and co‐workers review the recent development in stimuli‐responsive smart membranes for ...nanofiltration. The stimuli include pH, temperature, light, and electricity, which are introduced by size sieving, electrostatic repulsion, and wettability switching. This review also provides a critical analysis of the current advances in smart membranes and insights into remaining challenges and future directions.
Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy ...neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson's disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein-lipid compartmentalization not previously described in the Parkinsons' disease brain.
Tissue sculpting during development has been attributed mainly to cellular events through processes such as convergent extension or apical constriction
. However, recent work has revealed roles for ...basement membrane remodelling in global tissue morphogenesis
. Upon implantation, the epiblast and extraembryonic ectoderm of the mouse embryo become enveloped by a basement membrane. Signalling between the basement membrane and these tissues is critical for cell polarization and the ensuing morphogenesis
. However, the mechanical role of the basement membrane in post-implantation embryogenesis remains unknown. Here we demonstrate the importance of spatiotemporally regulated basement membrane remodelling during early embryonic development. Specifically, we show that Nodal signalling directs the generation and dynamic distribution of perforations in the basement membrane by regulating the expression of matrix metalloproteinases. This basement membrane remodelling facilitates embryo growth before gastrulation. The establishment of the anterior-posterior axis
further regulates basement membrane remodelling by localizing Nodal signalling-and therefore the activity of matrix metalloproteinases and basement membrane perforations-to the posterior side of the embryo. Perforations on the posterior side are essential for primitive-streak extension during gastrulation by rendering the basement membrane of the prospective primitive streak more prone to breaching. Thus spatiotemporally regulated basement membrane remodelling contributes to the coordination of embryo growth, morphogenesis and gastrulation.
Oil‐spill remediation is an international environmental challenge, and superamphiphilic membranes, as a promising solution, have recently drawn lots of attention. However, the robustness of the ...conventional membrane design is less satisfying under severe conditions during practical applications. Additionally, it is unavoidable for the membranes to face a series of foulants in their practical working environment, for example, algae and sand. These foulants will block the membrane, which leads to a new economic and environmental problem in terms of waste management at the end of their life. To address the aforementioned challenges, a new generation of superamphiphilic vitrimer epoxy resin membranes (SAVER) to separate oil and water efficiently is reported. Similar to classical epoxy resins, SAVER shows strong mechanical robustness and sustains exposure to aqua regia and sodium hydroxide solutions. Furthermore, the blocked membrane can be easily recovered when contaminated with mixed foulants by using dynamic transesterification reactions in the polymer network. The ease with which biobased SAVER can be manufactured, used, recycled, and re‐used without losing value points to new directions in designing a closed‐loop superamphiphilic membrane life cycle.
A new generation of biobased superamphiphilic vitrimer epoxy resin membranes to separate oil and water efficiently is reported. Similar to classical epoxy resins, this membrane shows strong mechanical robustness and sustains exposure to aqua regia and sodium hydroxide solutions. Furthermore, the blocked membrane can be easily recovered when contaminated with mixed foulants by using dynamic transesterification reactions.
Objectives
Artemisinin and artemisinin semi-synthetic derivatives (collectively known as endoperoxides) are first-line antimalarials for the treatment of uncomplicated and severe malaria. ...Endoperoxides display very fast killing rates and are generally recalcitrant to parasite resistance development. These key pharmacodynamic features are a result of a complex mechanism of action, the details of which lack consensus. Here, we report on the primary physiological events leading to parasite death.
Methods
Parasite mitochondrial (ΔΨm) and plasma membrane (ΔΨp) electrochemical potentials were measured using real-time single-cell imaging following exposure to pharmacologically relevant concentrations of endoperoxides (artemisinin, dihydroartemisinin, artesunate and the synthetic tetraoxane RKA182). In addition, mitochondrial electron transport chain components NADH:quinone oxidoreductase (alternative complex I), bc
1 (complex III) and cytochrome oxidase (complex IV) were investigated to determine their functional sensitivity to the various endoperoxides.
Results
Parasite exposure to endoperoxides resulted in rapid depolarization of parasite ΔΨm and ΔΨp. The rate of depolarization was decreased in the presence of a reactive oxygen species (ROS) scavenger and Fe3+ chelators. Depolarization of ΔΨm by endoperoxides is not believed to be through the inhibition of mitochondrial electron transport chain components, owing to the lack of significant inhibition when assayed directly.
Conclusions
The depolarization of ΔΨm and ΔΨp is shown to be mediated via the generation of ROS that are initiated by iron bioactivation of endoperoxides and/or catalysed by iron-dependent oxidative stress. These data are discussed in the context of current hypotheses concerning the mode of action of endoperoxides.
Extracellular vesicles, such as exosomes, can be used as interesting models to study the structure and function of biological membranes as these vesicles contain only one membrane (i.e., one lipid ...bilayer). In addition to lipids, they contain proteins, nucleic acids, and various other molecules. The lipid composition of exosomes is here compared to HIV particles and detergent-resistant membranes, which also have a high content of sphingolipids, cholesterol, and phosphatidylserine (PS). We discuss interactions between the lipids in the two bilayers, and especially those between PS 18:0/18:1 in the inner leaflet and the very-long-chain sphingolipids in the outer leaflet, and the importance of cholesterol for these interactions. We also briefly discuss the involvement of ether-linked phospholipids (PLs) in such lipid raft-like structures, and the possible involvement of these and other lipid classes in the formation of exosomes. The urgent need to improve the quality of quantitative lipidomic studies is highlighted.
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