-
Proceedings of the National Academy of... Jul 2023The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the...
The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the inner leaflet is composed of glycerophospholipids. This lipid asymmetry creates mechanical strength, lowers membrane permeability, and is necessary for virulence in many pathogens. Glycerophospholipids that mislocalize to the outer leaflet are removed by the Mla pathway, which consists of the outer membrane channel MlaA, the periplasmic lipid carrier MlaC, and the inner membrane transporter MlaBDEF. The opportunistic pathogen has two proteins of the MlaA family: PA2800 and PA3239. Here, we show that PA2800 is part of a canonical Mla pathway, while PA3239 functions with the putative lipase PA3238. While loss of either pathway individually has little to no effect on outer membrane integrity, loss of both pathways weakens the outer membrane permeability barrier and increases production of the secondary metabolite pyocyanin. We propose that mislocalized glycerophospholipids are removed from the outer leaflet by PA3239 (renamed MlaZ), transferred to PA3238 (renamed MlaY), and degraded. This pathway streamlines recycling of glycerophospholipid degradation products by removing glycerophospholipids from the outer leaflet prior to degradation.
Topics: Membrane Lipids; Pseudomonas aeruginosa; Biological Transport; Phospholipases; Bacterial Outer Membrane Proteins; Cell Membrane; Glycerophospholipids
PubMed: 37463202
DOI: 10.1073/pnas.2302546120 -
Biochimica Et Biophysica Acta.... Aug 2023Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Mitochondrial Membranes; Mitochondria; Endoplasmic Reticulum
PubMed: 37044239
DOI: 10.1016/j.bbadis.2023.166716 -
Applied Microbiology and Biotechnology Mar 2024Extremotolerant and extremophilic fungi are an important part of microbial communities that thrive in extreme environments. Among them, the black yeasts are particularly... (Review)
Review
Extremotolerant and extremophilic fungi are an important part of microbial communities that thrive in extreme environments. Among them, the black yeasts are particularly adaptable. They use their melanized cell walls and versatile morphology, as well as a complex set of molecular adaptations, to survive in conditions that are lethal to most other species. In contrast to extremophilic bacteria and archaea, these fungi are typically extremotolerant rather than extremophilic and exhibit an unusually wide ecological amplitude. Some extremely halotolerant black yeasts can grow in near-saturated NaCl solutions, but can also grow on normal mycological media. They adapt to the low water activity caused by high salt concentrations by sensing their environment, balancing osmotic pressure by accumulating compatible solutes, removing toxic salt ions from the cell using membrane transporters, altering membrane composition and remodelling the highly melanized cell wall. As protection against extreme conditions, halotolerant black yeasts also develop different morphologies, from yeast-like to meristematic. Genomic studies of black yeasts have revealed a variety of reproductive strategies, from clonality to intense recombination and the formation of stable hybrids. Although a comprehensive understanding of the ecological role and molecular adaptations of halotolerant black yeasts remains elusive and the application of many experimental methods is challenging due to their slow growth and recalcitrant cell walls, much progress has been made in deciphering their halotolerance. Advances in molecular tools and genomics are once again accelerating the research of black yeasts, promising further insights into their survival strategies and the molecular basis of their adaptations. KEY POINTS: • Black yeasts show remarkable adaptability to environmental stress • Black yeasts are part of microbial communities in hypersaline environments • Halotolerant black yeasts utilise various molecular and morphological adaptations.
Topics: Ascomycota; Saccharomyces cerevisiae; Archaea; Cell Wall; Extreme Environments; Extremophiles
PubMed: 38441672
DOI: 10.1007/s00253-024-13052-2 -
Biochimica Et Biophysica Acta.... Aug 2023Membrane trafficking is essential to maintain the spatiotemporal control of protein and lipid distribution within membrane systems of eukaryotic cells. To achieve their... (Review)
Review
Membrane trafficking is essential to maintain the spatiotemporal control of protein and lipid distribution within membrane systems of eukaryotic cells. To achieve their functional destination proteins are sorted and transported into lipid carriers that construct the secretory and endocytic pathways. It is an emerging theme that lipid diversity might exist in part to ensure the homeostasis of these pathways. Sphingolipids, a chemical diverse type of lipids with special physicochemical characteristics have been implicated in the selective transport of proteins. In this review, we will discuss current knowledge about how sphingolipids modulate protein trafficking through the endomembrane systems to guarantee that proteins reach their functional destination and the proposed underlying mechanisms.
Topics: Sphingolipids; Biological Transport; Protein Transport; Membranes
PubMed: 37201864
DOI: 10.1016/j.bbalip.2023.159334 -
The Journal of Biological Chemistry Sep 2023α-Synuclein and family members β- and γ-synuclein are presynaptic proteins that sense and generate membrane curvature, properties important for synaptic vesicle (SV)...
α-Synuclein and family members β- and γ-synuclein are presynaptic proteins that sense and generate membrane curvature, properties important for synaptic vesicle (SV) cycling. αβγ-synuclein triple knockout neurons exhibit SV endocytosis deficits. Here, we investigated if α-synuclein affects clathrin assembly in vitro. Visualizing clathrin assembly on membranes using a lipid monolayer system revealed that α-synuclein increases clathrin lattices size and curvature. On cell membranes, we observe that α-synuclein is colocalized with clathrin and its adapter AP180 in a concentric ring pattern. Clathrin puncta that contain both α-synuclein and AP180 were significantly larger than clathrin puncta containing either protein alone. We determined that this effect occurs in part through colocalization of α-synuclein with the phospholipid PI(4,5)P2 in the membrane. Immuno-electron microscopy (EM) of synaptosomes uncovered that α-synuclein relocalizes from SVs to the presynaptic membrane upon stimulation, positioning α-synuclein to function on presynaptic membranes during or after stimulation. Additionally, we show that deletion of synucleins impacts brain-derived clathrin-coated vesicle size. Thus, α-synuclein affects the size and curvature of clathrin structures on membranes and functions as an endocytic accessory protein.
Topics: alpha-Synuclein; Cell Membrane; Clathrin; Endocytosis; Microscopy, Immunoelectron; Monomeric Clathrin Assembly Proteins; Neurons; Presynaptic Terminals; Synaptosomes; Protein Transport; In Vitro Techniques; Phosphatidylinositol 4,5-Diphosphate; Brain; Clathrin-Coated Vesicles
PubMed: 37516240
DOI: 10.1016/j.jbc.2023.105091 -
Journal of Nephrology Nov 2023Hydroxychloroquine is one of the oldest disease-modifying anti-rheumatic drugs in clinical use. The drug interferes with lysosomal activity and antigen presentation,... (Review)
Review
Hydroxychloroquine is one of the oldest disease-modifying anti-rheumatic drugs in clinical use. The drug interferes with lysosomal activity and antigen presentation, inhibits autophagy, and decreases transcription of pro-inflammatory cytokines. Owing to its immunomodulatory, anti-inflammatory, anti-thrombotic effect, hydroxychloroquine has been an integral part of therapy for systemic lupus erythematosus and lupus nephritis for several decades. The therapeutic versatility of hydroxychloroquine has led to repurposing it for other clinical conditions, with recent studies showing reduction in proteinuria in IgA nephropathy. Research is also underway to investigate the efficacy of hydroxychloroquine in primary membranous nephropathy, Alport's syndrome, systemic vasculitis, anti-GBM disease, acute kidney injury and for cardiovascular risk reduction in chronic kidney disease. Hydroxychloroquine is well-tolerated, inexpensive, and widely available and therefore, should its indications expand in the future, it would certainly be welcomed. However, clinicians should be aware of the risk of irreversible and progressive retinal toxicity and rarely, cardiomyopathy. Monitoring hydroxychloroquine levels in blood appears to be a promising tool to evaluate compliance, individualize the dose and reduce the risk of retinal toxicity, although this is not yet standard clinical practice. In this review, we discuss the existing knowledge regarding the mechanism of action of hydroxychloroquine, its utility in lupus nephritis and other kidney diseases, the main adverse effects and the evidence gaps that need to be addressed in future research. Created with Biorender.com. HCQ, hydroxychloroquine; GBM, glomerular basement membrane; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; TLR, toll-like receptor.
Topics: Humans; Hydroxychloroquine; Lupus Nephritis; Nephrology; Antirheumatic Agents; Lupus Erythematosus, Systemic
PubMed: 37530940
DOI: 10.1007/s40620-023-01733-6 -
Frontiers in Immunology 2023Gasdermins comprise a family of pore-forming proteins, which play critical roles in (auto)inflammatory diseases and cancer. They are expressed as self-inhibited... (Review)
Review
Gasdermins comprise a family of pore-forming proteins, which play critical roles in (auto)inflammatory diseases and cancer. They are expressed as self-inhibited precursor proteins consisting of an aminoterminal cytotoxic effector domain (NT-GSDM) and a carboxyterminal inhibitor domain (GSDM-CT) separated by an unstructured linker region. Proteolytic processing in the linker region liberates NT-GSDM, which translocates to membranes, forms oligomers, and induces membrane permeabilization, which can disturb the cellular equilibrium that can lead to cell death. Gasdermin activation and pore formation are associated with inflammation, particularly when induced by the inflammatory protease caspase-1 upon inflammasome activation. These gasdermin pores allow the release of the pro-inflammatory cytokines interleukin(IL)-1β and IL-18 and induce a lytic type of cell death, termed pyroptosis that supports inflammation, immunity, and tissue repair. However, even at the cellular level, the consequences of gasdermin activation are diverse and range from induction of programmed cell death - pyroptosis or apoptosis - to poorly characterized protective mechanisms. The specific effects of gasdermin activation can vary between species, cell types, the membrane that is being permeabilized (plasma membrane, mitochondrial membrane, etc.), and the overall biological state of the local tissue/cells. In epithelia, gasdermins seem to play crucial roles. Keratinocytes represent the main cell type of the epidermis, which is the outermost skin layer with an essential barrier function. Compared to other tissues, keratinocytes express all members of the gasdermin family, in part in a differentiation-specific manner. That raises questions regarding the specific roles of individual GSDM family members in the skin, the mechanisms and consequences of their activation, and the potential crosstalk between them. In this review, we summarize the current knowledge about gasdermins with a focus on keratinocytes and the skin and discuss the possible roles of the different family members in immunity and disease.
PubMed: 37771587
DOI: 10.3389/fimmu.2023.1254150 -
Hormone and Metabolic Research =... Dec 2023The involvements of iron metabolism, lipid peroxidation, and oxidative stress in Alzheimer's disease (AD) development have recently received a lot of attention. We also...
The involvements of iron metabolism, lipid peroxidation, and oxidative stress in Alzheimer's disease (AD) development have recently received a lot of attention. We also observe that these pathogenic occurrences play a key role in regulating ferroptosis, a unique regulatory cell death that is iron-dependent, oxidative, and non-apoptotic. Iron is a crucial component that makes up a subunit of the oxidase responsible for lipid peroxidation. A family of non-heme iron enzymes known as lipoxygenases (LOXs) can cause ferroptosis by oxidising polyunsaturated fatty acids in cellular membranes (PUFAs). Toxic lipid hydroperoxides are produced in large part by the iron in LOX active sites. Deferoxamine and deferiprone, two iron chelators, could also treat ferroptosis by eliminating the crucial catalytic iron from LOXs. Phospholipids containing polyunsaturated fatty acids are the main substrates of lipid peroxidation in ferroptosis, which is favourably controlled by enzymes like ACSL4, LPCAT3, ALOXs, or POR. Selective stimulation of autophagic degradation pathways leads to an increase in iron accumulation and lipid peroxidation, which promotes ferroptosis. We highlighted recent advancements in our understanding of ferroptosis signaling routes in this study. One form of regulated necrotic cell death known as ferroptosis has been linked to a number of diseases, including cancer, neurological disorders, and ischemia/reperfusion injury. Cerebrospinal fluid (CSF) ferritin may be a good indicator of the amount of iron in the brain because it is the main protein that stores iron.
Topics: Humans; Ferroptosis; Alzheimer Disease; Lipid Peroxidation; Iron; Fatty Acids, Unsaturated; Signal Transduction
PubMed: 37257500
DOI: 10.1055/a-2084-3561