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Cell Nov 2021Biofilms are community architectures adopted by bacteria inclusive of a self-formed extracellular matrix that protects resident bacteria from diverse environmental...
Biofilms are community architectures adopted by bacteria inclusive of a self-formed extracellular matrix that protects resident bacteria from diverse environmental stresses and, in many species, incorporates extracellular DNA (eDNA) and DNABII proteins for structural integrity throughout biofilm development. Here, we present evidence that this eDNA-based architecture relies on the rare Z-form. Z-form DNA accumulates as biofilms mature and, through stabilization by the DNABII proteins, confers structural integrity to the biofilm matrix. Indeed, substances known to drive B-DNA into Z-DNA promoted biofilm formation whereas those that drive Z-DNA into B-DNA disrupted extant biofilms. Importantly, we demonstrated that the universal bacterial DNABII family of proteins stabilizes both bacterial- and host-eDNA in the Z-form in situ. A model is proposed that incorporates the role of Z-DNA in biofilm pathogenesis, innate immune response, and immune evasion.
Topics: Animals; Antibody Specificity; Bacteria; Bacterial Proteins; Biofilms; Cell Line; Chinchilla; DNA, Bacterial; DNA, Cruciform; Deoxyribonucleases; Extracellular Matrix; Extracellular Space; Extracellular Traps; Humans; Tetradecanoylphorbol Acetate
PubMed: 34735796
DOI: 10.1016/j.cell.2021.10.010 -
The Journal of Cell Biology Apr 2022Genetic, environmental, and aging-related insults can promote the misfolding and subsequent aggregation of secreted proteins implicated in the pathogenesis of numerous... (Review)
Review
Genetic, environmental, and aging-related insults can promote the misfolding and subsequent aggregation of secreted proteins implicated in the pathogenesis of numerous diseases. This has led to considerable interest in understanding the molecular mechanisms responsible for regulating proteostasis in extracellular environments such as the blood and cerebrospinal fluid (CSF). Extracellular proteostasis is largely dictated by biological pathways comprising chaperones, folding enzymes, and degradation factors localized to the ER and extracellular space. These pathways limit the accumulation of nonnative, potentially aggregation-prone proteins in extracellular environments. Many reviews discuss the molecular mechanisms by which these pathways impact the conformational integrity of the secreted proteome. Here, we instead focus on describing the stress-responsive mechanisms responsible for adapting ER and extracellular proteostasis pathways to protect the secreted proteome from pathologic insults that challenge these environments. Further, we highlight new strategies to identify stress-responsive pathways involved in regulating extracellular proteostasis and describe the pathologic and therapeutic implications for these pathways in human disease.
Topics: Animals; Endoplasmic Reticulum; Extracellular Space; Humans; Molecular Chaperones; Proteostasis; Stress, Physiological; Unfolded Protein Response
PubMed: 35191945
DOI: 10.1083/jcb.202112104 -
Anatomical Record (Hoboken, N.J. : 2007) Jan 2019The space between cardiac myocytes is commonly referred-to as the cardiac interstitium (CI). The CI is a unique, complex and dynamic microenvironment in which multiple... (Review)
Review
The space between cardiac myocytes is commonly referred-to as the cardiac interstitium (CI). The CI is a unique, complex and dynamic microenvironment in which multiple cell types, extracellular matrix molecules, and instructive signals interact to crucially support heart homeostasis and promote cardiac responses to normal and pathologic stimuli. Despite the biomedical and clinical relevance of the CI, its detailed cellular structure remains to be elucidated. In this review, we will dissect the organization of the cardiac interstitium by following its changing cellular and molecular composition from embryonic developmental stages to adulthood, providing a systematic analysis of the biological components of the CI. The main goal of this review is to contribute to our understanding of the CI roles in health and disease. Anat Rec, 302:58-68, 2019. © 2018 Wiley Periodicals, Inc.
Topics: Animals; Embryonic Development; Extracellular Space; Humans; Myocardium
PubMed: 30288955
DOI: 10.1002/ar.23915 -
Cell Reports May 2023The extracellular space (ECS) and its constituents play a crucial role in brain development, plasticity, circadian rhythm, and behavior, as well as brain diseases. Yet,...
The extracellular space (ECS) and its constituents play a crucial role in brain development, plasticity, circadian rhythm, and behavior, as well as brain diseases. Yet, since this compartment has an intricate geometry and nanoscale dimensions, its detailed exploration in live tissue has remained an unmet challenge. Here, we used a combination of single-nanoparticle tracking and super-resolution microscopy approaches to map the nanoscale dimensions of the ECS across the rodent hippocampus. We report that these dimensions are heterogeneous between hippocampal areas. Notably, stratum radiatum CA1 and CA3 ECS differ in several characteristics, a difference that gets abolished after digestion of the extracellular matrix. The dynamics of extracellular immunoglobulins vary within these areas, consistent with their distinct ECS characteristics. Altogether, we demonstrate that ECS nanoscale anatomy and diffusion properties are widely heterogeneous across hippocampal areas, impacting the dynamics and distribution of extracellular molecules.
Topics: Humans; Extracellular Space; Hippocampus; Diffusion; Extracellular Matrix; Brain Diseases
PubMed: 37149864
DOI: 10.1016/j.celrep.2023.112478 -
Neurobiology of Disease Feb 2023The brain extracellular space (ECS) is a vast interstitial reticulum of extreme morphological complexity, composed of narrow gaps separated by local expansions, enabling... (Review)
Review
The brain extracellular space (ECS) is a vast interstitial reticulum of extreme morphological complexity, composed of narrow gaps separated by local expansions, enabling interconnected highways between neural cells. Constituting on average 20% of brain volume, the ECS is key for intercellular communication, and understanding its diffusional properties is of paramount importance for understanding the brain. Within the ECS, neuroactive substances travel predominantly by diffusion, spreading through the interstitial fluid and the extracellular matrix scaffold after being focally released. The nanoscale dimensions of the ECS render it unresolvable by conventional live tissue compatible imaging methods, and historically diffusion of tracers has been used to indirectly infer its structure. Novel nanoscopic imaging techniques now show that the ECS is a highly dynamic compartment, and that diffusivity in the ECS is more heterogeneous than anticipated, with great variability across brain regions and physiological states. Diffusion is defined primarily by the local ECS geometry, and secondarily by the viscosity of the interstitial fluid, including the obstructive and binding properties of the extracellular matrix. ECS volume fraction and tortuosity both strongly determine diffusivity, and each can be independently regulated e.g. through alterations in glial morphology and the extracellular matrix composition. Here we aim to provide an overview of our current understanding of the ECS and its diffusional properties. We highlight emerging technological advances to respectively interrogate and model diffusion through the ECS, and point out how these may contribute in resolving the remaining enigmas of the ECS.
Topics: Extracellular Space; Brain; Extracellular Matrix; Neuroglia; Neurons
PubMed: 36581229
DOI: 10.1016/j.nbd.2022.105981 -
Frontiers in Immunology 2022Posttranslational modifications (PTMs) allow to control molecular and cellular functions in response to specific signals and changes in the microenvironment of cells.... (Review)
Review
Posttranslational modifications (PTMs) allow to control molecular and cellular functions in response to specific signals and changes in the microenvironment of cells. They regulate structure, localization, stability, and function of proteins in a spatial and temporal manner. Among them, specific thiol modifications of cysteine (Cys) residues facilitate rapid signal transduction. In fact, Cys is unique because it contains the highly reactive thiol group that can undergo different reversible and irreversible modifications. Upon inflammation and changes in the cellular microenvironment, many extracellular soluble and membrane proteins undergo thiol modifications, particularly dithiol-disulfide exchange, S-glutathionylation, and S-nitrosylation. Among others, these thiol switches are essential for inflammatory signaling, regulation of gene expression, cytokine release, immunoglobulin function and isoform variation, and antigen presentation. Interestingly, also the redox state of bacterial and viral proteins depends on host cell-mediated redox reactions that are critical for invasion and infection. Here, we highlight mechanistic thiol switches in inflammatory pathways and infections including cholera, diphtheria, hepatitis, human immunodeficiency virus (HIV), influenza, and coronavirus disease 2019 (COVID-19).
Topics: COVID-19; Cysteine; Extracellular Space; Humans; Inflammation; Proteins; Sulfhydryl Compounds
PubMed: 35833136
DOI: 10.3389/fimmu.2022.932525 -
Frontiers in Immunology 2023Nicotinamide phosphoribosyltransferase (NAMPT) plays a central role in mammalian cell metabolism by contributing to nicotinamide adenine dinucleotide biosynthesis.... (Review)
Review
Nicotinamide phosphoribosyltransferase (NAMPT) plays a central role in mammalian cell metabolism by contributing to nicotinamide adenine dinucleotide biosynthesis. However, NAMPT activity is not limited to the intracellular compartment, as once secreted, the protein accomplishes diverse functions in the extracellular space. Extracellular NAMPT (eNAMPT, also called visfatin or pre-B-cell colony enhancing factor) has been shown to possess adipocytokine, pro-inflammatory, and pro-angiogenic activities. Numerous studies have reported the association between elevated levels of circulating eNAMPT and various inflammatory and metabolic disorders such as obesity, diabetes, atherosclerosis, arthritis, inflammatory bowel disease, lung injury and cancer. In this review, we summarize the current state of knowledge on eNAMPT biology, proposed roles in disease pathogenesis, and its potential as a disease biomarker. We also briefly discuss the emerging therapeutic approaches for eNAMPT inhibition.
Topics: Animals; Humans; Nicotinamide Phosphoribosyltransferase; Diabetes Mellitus; Extracellular Space; Neoplasms; Biomarkers; Mammals
PubMed: 37915565
DOI: 10.3389/fimmu.2023.1268756 -
Journal of Innate Immunity 2009
Topics: Animals; Cellular Structures; DNA; Extracellular Space; Humans; Immunoproteins; Mice; Neutrophil Activation; Neutrophils
PubMed: 20375574
DOI: 10.1159/000207015 -
The Journal of Neuroscience : the... Oct 2020The extracellular space (ECS) plays an important role in the physiology of neural circuits. Despite our detailed understanding of the cellular architecture of the...
The extracellular space (ECS) plays an important role in the physiology of neural circuits. Despite our detailed understanding of the cellular architecture of the mammalian retina, little is known about the organization and dynamics of the retinal ECS. We developed an optical technique based on two-photon imaging of fluorescently labeled extracellular fluid to measure the ECS volume fraction (α) in the retina of male and female mice. This method has high spatial resolution and can detect rapid changes in α evoked by osmotic challenge and neuronal activity. The measured ECS α varied dramatically in different layers of the adult mouse retina, with α equaling ∼0.050 in the ganglion cell layer, ∼0.122 in the inner plexiform layer (IPL), ∼0.025 in the inner nuclear layer (INL), ∼0.087 in the outer plexiform layer, and ∼0.026 in the outer nuclear layer (ONL). ECS α was significantly larger early in retinal development; α was 67% larger in the IPL and 100% larger in the INL in neonatal mice compared with adults. In adult retinas, light stimulation evoked rapid decreases in ECS α. Light-driven reductions in ECS α were largest in the IPL, where visual stimuli decreased α values ∼10%. These light-evoked decreases demonstrate that a physiological stimulus can lead to rapid changes in ECS α and indicate that activity-dependent regulation of extracellular space may contribute to visual processing in the retina. The volume fraction of the extracellular space (ECS α), that portion of CNS tissue occupied by interstitial space, influences the diffusion of neurotransmitters from the synaptic cleft and the volume transmission of transmitters. However, ECS α has never been measured in live retina, and little is known about how ECS α varies following physiological stimulation. Here we show that ECS α values vary dramatically between different retinal layers and decrease by 10% following light stimulation. ECS α differences within the retina will influence volume transmission and light-evoked α variations may modulate synaptic transmission and visual processing in the retina. Activity-dependent ECS α variations may represent a mechanism of synaptic modulation throughout the CNS.
Topics: Absorptiometry, Photon; Animals; Animals, Newborn; Extracellular Space; Female; Fluorescent Dyes; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Neurons; Osmotic Pressure; Photic Stimulation; Retina; Retinal Ganglion Cells
PubMed: 32887746
DOI: 10.1523/JNEUROSCI.1717-20.2020 -
The Journal of Physiology Jun 2011
Topics: Animals; Extracellular Fluid; Extracellular Space; Humans; Models, Biological
PubMed: 21540347
DOI: 10.1113/jphysiol.2011.211268