10 research outputs found
The vimentin cytoskeleton: when polymer physics meets cell biology
The proper functions of tissues depend on the ability of cells to withstand stress and maintain shape. Central to this process is the cytoskeleton, comprised of three polymeric networks: F-actin, microtubules, and intermediate filaments (IFs). IF proteins are among the most abundant cytoskeletal proteins in cells; yet they remain some of the least understood. Their structure and function deviate from those of their cytoskeletal partners, F-actin and microtubules. IF networks show a unique combination of extensibility, flexibility and toughness that confers mechanical resilience to the cell. Vimentin is an IF protein expressed in mesenchymal cells. This review highlights exciting new results on the physical biology of vimentin intermediate filaments and their role in allowing whole cells and tissues to cope with stress
Exercise-Induced Protection Against Reperfusion Arrhythmia Involves Stabilization of Mitochondrial Energetics
Mitochondria influence cardiac electrophysiology through energy- and redox-sensitive ion channels in the sarcolemma, with the collapse of energetics believed to be centrally involved in arrhythmogenesis. This study was conducted to determine if preservation of mitochondrial membrane potential (ΔΨ(m)) contributes to the antiarrhythmic effect of exercise. We utilized perfused hearts, isolated myocytes, and isolated mitochondria exposed to metabolic challenge to determine the effects of exercise on cardiac mitochondria. Hearts from sedentary (Sed) and exercised (Ex; 10 days of treadmill running) Sprague-Dawley rats were perfused on a two-photon microscope stage for simultaneous measurement of ΔΨ(m) and ECG. After ischemia-reperfusion, the collapse of ΔΨ(m) was commensurate with the onset of arrhythmia. Exercise preserved ΔΨ(m) and decreased the incidence of fibrillation/tachycardia (P < 0.05). Our findings in intact hearts were corroborated in isolated myocytes exposed to in vitro hypoxia-reoxygenation, with Ex rats demonstrating enhanced redox control and sustained ΔΨ(m) during reoxygenation. Finally, we induced anoxia-reoxygenation in isolated mitochondria using high-resolution respirometry with simultaneous measurement of respiration and H(2)O(2). Mitochondria from Ex rats sustained respiration with lower rates of H(2)O(2) emission than Sed rats. Exercise helps sustain postischemic mitochondrial bioenergetics and redox homeostasis, which is associated with preserved ΔΨ(m) and protection against reperfusion arrhythmia. The reduction of fatal ventricular arrhythmias through exercise-induced mitochondrial adaptations indicates that mitochondrial therapeutics may be an effective target for the treatment of heart disease
Extracellular Vimentin as a Target Against SARS-CoV-2 Host Cell Invasion
Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. The primary receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2), yet new studies reveal the importance of additional extracellular co-receptors that mediate binding and host cell invasion by SARS-CoV-2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens’ cellular uptake. Biophysical and cell infection studies are done to determine whether vimentin might bind SARS-CoV-2 and facilitate its uptake. Dynamic light scattering shows that vimentin binds to pseudovirus coated with the SARS-CoV-2 spike protein, and antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cells. The results are consistent with a model in which extracellular vimentin acts as a co-receptor for SARS-CoV-2 spike protein with a binding affinity less than that of the spike protein with ACE2. Extracellular vimentin may thus serve as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry, and vimentin-targeting agents may yield new therapeutic strategies for preventing and slowing SARS-CoV-2 infection
Extracellular vimentin is sufficient to promote cell attachment, spreading, and motility by a mechanism involving N-acetyl glucosamine-containing structures
Vimentin intermediate !laments form part of the cytoskeleton
of mesenchymal cells, but under pathological conditions often
associatedwith in ammation, vimentin !laments depolymerize as
the result of phosphorylation or citrullination, and vimentin
oligomers are secreted or released into the extracellular environment.
In the extracellular space, vimentin can bind surfaces of cells
and the extracellular matrix, and the interaction between extracellular
vimentin and cells can trigger changes in cellular functions,
such as activation of !broblasts to a !brotic phenotype. The
mechanism by which extracellular vimentin binds external cell
membranes and whether vimentin alone can act as an adhesive
anchor for cells is largely uncharacterized. Here, we show that
various cell types (normal and vimentin null !broblasts, mesenchymal
stem cells, and A549 lung carcinoma cells) attach to and
spread on polyacrylamide hydrogel substrates covalently linked to
vimentin. Using traction force microscopy and spheroid expansion
assays, we characterize how different cell types respond to
extracellular vimentin. Cell attachment to and spreading on
vimentin-coated surfaces is inhibited by hyaluronic acid degrading
enzymes, hyaluronic acid synthase inhibitors, soluble heparin
or N-acetyl glucosamine, all of which are treatments that have
little or no effect on the same cell types binding to collagen-coated
hydrogels. These studies highlight the effectiveness of substratebound
vimentin as a ligand for cells and suggest that carbohydrate
structures, including the glycocalyx and glycosylated cell
surface proteins that contain N-acetyl glucosamine, form a novel
class of adhesion receptors for extracellular vimentin that can
either directly support cell adhesion to a substrate or !ne-tune the
glycocalyx adhesive properties