Discovery of Trametinib as an orchestrator for cytoskeletal vimentin remodeling.

The dynamic remodeling of the cytoskeletal network of vimentin intermediate filaments network supports various cellular functions, including cell morphology, elasticity, migration, organelle localization, and resistance against mechanical or pathological stress. Currently available chemicals targeting vimentin predominantly induce network reorganization and shrinkage around the nucleus. Effective tools for long-term manipulation of vimentin network dispersion in living cells are still lacking, limiting in-depth studies on vimentin function and potential therapeutic applications. Here, we verified that a commercially available small molecule, Trametinib, is capable of inducing spatial spreading of the cellular vimentin network without affecting its transcriptional or translational regulation. Further evidence confirmed its low cytotoxicity and similar effects on different cell types. Importantly, Trametinib has no impact on the other two cytoskeletal systems, actin filaments and the microtubule network. Moreover, Trametinib regulates vimentin network dispersion rapidly and efficiently, with effects persisting for up to 48 h after drug withdrawal. We also ruled out the possibility that Trametinib directly affects the phosphorylation level of vimentin. In summary, we identified an unprecedented regulator, Trametinib, capable of spreading the vimentin network toward the cell periphery, and thus complemented the existing repertoire of vimentin remodeling drugs in the field of cytoskeletal research.

Impairment of Assembly of the Vimentin Intermediate Filaments Leads to Suppression of Formation and Maturation of Focal Contacts and Alteration of the Type of Cellular Protrusions.

Cell migration is largely determined by the type of protrusions formed by the cell. Mesenchymal migration is accomplished by formation of lamellipodia and/or filopodia, while amoeboid migration is based on bleb formation. Changing of migrational conditions can lead to alteration in the character of cell movement. For example, inhibition of the Arp2/3-dependent actin polymerization by the CK-666 inhibitor leads to transition from mesenchymal to amoeboid motility mode. Ability of the cells to switch from one type of motility to another is called migratory plasticity. Cellular mechanisms regulating migratory plasticity are poorly understood. One of the factors determining the possibility of migratory plasticity may be the presence and/or organization of vimentin intermediate filaments (VIFs). To investigate whether organization of the VIF network affects the ability of fibroblasts to form membrane blebs, we used rat embryo fibroblasts REF52 with normal VIF organization, fibroblasts with vimentin knockout (REF-/-), and fibroblasts with mutation inhibiting assembly of the full-length VIFs (REF117). Blebs formation was induced by treatment of cells with CK-666. Vimentin knockout did not lead to statistically significant increase in the number of cells with blebs. The fibroblasts with short fragments of vimentin demonstrate the significant increase in number of cells forming blebs both spontaneously and in the presence of CK-666. Disruption of the VIF organization did not lead to the significant changes in the microtubules network or the level of myosin light chain phosphorylation, but caused significant reduction in the focal contact system. The most pronounced and statistically significant decrease in both size and number of focal adhesions were observed in the REF117 cells. We believe that regulation of the membrane blebbing by VIFs is mediated by their effect on the focal adhesion system. Analysis of migration of fibroblasts with different organization of VIFs in a three-dimensional collagen gel showed that organization of VIFs determines the type of cell protrusions, which, in turn, determines the character of cell movement. A novel role of VIFs as a regulator of membrane blebbing, essential for manifestation of the migratory plasticity, is shown.

Type III intermediate filaments in redox interplay: key role of the conserved cysteine residue.

Intermediate filaments (IFs) are cytoskeletal elements involved in mechanotransduction and in the integration of cellular responses. They are versatile structures and their assembly and organization are finely tuned by posttranslational modifications. Among them, type III IFs, mainly vimentin, have been identified as targets of multiple oxidative and electrophilic modifications. A characteristic of most type III IF proteins is the presence in their sequence of a single, conserved cysteine residue (C328 in vimentin), that is a hot spot for these modifications and appears to play a key role in the ability of the filament network to respond to oxidative stress. Current structural models and experimental evidence indicate that this cysteine residue may occupy a strategic position in the filaments in such a way that perturbations at this site, due to chemical modification or mutation, impact filament assembly or organization in a structure-dependent manner. Cysteine-dependent regulation of vimentin can be modulated by interaction with divalent cations, such as zinc, and by pH. Importantly, vimentin remodeling induced by C328 modification may affect its interaction with cellular organelles, as well as the cross-talk between cytoskeletal networks, as seems to be the case for the reorganization of actin filaments in response to oxidants and electrophiles. In summary, the evidence herein reviewed delineates a complex interplay in which type III IFs emerge both as targets and modulators of redox signaling.

Plectin plays a role in the migration and volume regulation of astrocytes: a potential biomarker of glioblastoma.

BACKGROUND: The expression of aquaporin 4 (AQP4) and intermediate filament (IF) proteins is altered in malignant glioblastoma (GBM), yet the expression of the major IF-based cytolinker, plectin (PLEC), and its contribution to GBM migration and invasiveness, are unknown. Here, we assessed the contribution of plectin in affecting the distribution of plasmalemmal AQP4 aggregates, migratory properties, and regulation of cell volume in astrocytes. METHODS: In human GBM, the expression of glial fibrillary acidic protein (GFAP), AQP4 and PLEC transcripts was analyzed using publicly available datasets, and the colocalization of PLEC with AQP4 and with GFAP was determined by immunohistochemistry. We performed experiments on wild-type and plectin-deficient primary and immortalized mouse astrocytes, human astrocytes and permanent cell lines (U-251 MG and T98G) derived from a human malignant GBM. The expression of plectin isoforms in mouse astrocytes was assessed by quantitative real-time PCR. Transfection, immunolabeling and confocal microscopy were used to assess plectin-induced alterations in the distribution of the cytoskeleton, the influence of plectin and its isoforms on the abundance and size of plasmalemmal AQP4 aggregates, and the presence of plectin at the plasma membrane. The release of plectin from cells was measured by ELISA. The migration and dynamics of cell volume regulation of immortalized astrocytes were assessed by the wound-healing assay and calcein labeling, respectively. RESULTS: A positive correlation was found between plectin and AQP4 at the level of gene expression and protein localization in tumorous brain samples. Deficiency of plectin led to a decrease in the abundance and size of plasmalemmal AQP4 aggregates and altered distribution and bundling of the cytoskeleton. Astrocytes predominantly expressed P1c, P1e, and P1g plectin isoforms. The predominant plectin isoform associated with plasmalemmal AQP4 aggregates was P1c, which also affected the mobility of astrocytes most prominently. In the absence of plectin, the collective migration of astrocytes was impaired and the dynamics of cytoplasmic volume changes in peripheral cell regions decreased. Plectin's abundance on the plasma membrane surface and its release from cells were increased in the GBM cell lines. CONCLUSIONS: Plectin affects cellular properties that contribute to the pathology of GBM. The observed increase in both cell surface and released plectin levels represents a potential biomarker and therapeutic target in the diagnostics and treatment of GBMs.

Plasma Membrane Blebbing Is Controlled by Subcellular Distribution of Vimentin Intermediate Filaments.

The formation of specific cellular protrusions, plasma membrane blebs, underlies the amoeboid mode of cell motility, which is characteristic for free-living amoebae and leukocytes, and can also be adopted by stem and tumor cells to bypass unfavorable migration conditions and thus facilitate their long-distance migration. Not all cells are equally prone to bleb formation. We have previously shown that membrane blebbing can be experimentally induced in a subset of HT1080 fibrosarcoma cells, whereas other cells in the same culture under the same conditions retain non-blebbing mesenchymal morphology. Here we show that this heterogeneity is associated with the distribution of vimentin intermediate filaments (VIFs). Using different approaches to alter the VIF organization, we show that blebbing activity is biased toward cell edges lacking abundant VIFs, whereas the VIF-rich regions of the cell periphery exhibit low blebbing activity. This pattern is observed both in interphase fibroblasts, with and without experimentally induced blebbing, and during mitosis-associated blebbing. Moreover, the downregulation of vimentin expression or displacement of VIFs away from the cell periphery promotes blebbing even in cells resistant to bleb-inducing treatments. Thus, we reveal a new important function of VIFs in cell physiology that involves the regulation of non-apoptotic blebbing essential for amoeboid cell migration and mitosis.

Desmin and its molecular chaperone, the αB-crystallin: How post-translational modifications modulate their functions in heart and skeletal muscles?

Maintenance of the highly organized striated muscle tissue requires a cell-wide dynamic network through protein-protein interactions providing an effective mechanochemical integrator of morphology and function. Through a continuous and complex trans-cytoplasmic network, desmin intermediate filaments ensure this essential role in heart and in skeletal muscle. Besides their role in the maintenance of cell shape and architecture (permitting contractile activity efficiency and conferring resistance towards mechanical stress), desmin intermediate filaments are also key actors of cell and tissue homeostasis. Desmin participates to several cellular processes such as differentiation, apoptosis, intracellular signalisation, mechanotransduction, vesicle trafficking, organelle biogenesis and/or positioning, calcium homeostasis, protein homeostasis, cell adhesion, metabolism and gene expression. Desmin intermediate filaments assembly requires αB-crystallin, a small heat shock protein. Over its chaperone activity, αB-crystallin is involved in several cellular functions such as cell integrity, cytoskeleton stabilization, apoptosis, autophagy, differentiation, mitochondria function or aggresome formation. Importantly, both proteins are known to be strongly associated to the aetiology of several cardiac and skeletal muscles pathologies related to desmin filaments disorganization and a strong disturbance of desmin interactome. Note that these key proteins of cytoskeleton architecture are extensively modified by post-translational modifications that could affect their functional properties. Therefore, we reviewed in the herein paper the impact of post-translational modifications on the modulation of cellular functions of desmin and its molecular chaperone, the αB-crystallin.

Considering impact of age and sex on cardiac cytoskeletal components.

The cardiac cytoskeletal components are integral to cardiomyocyte function and are responsible for contraction, sustaining cell structure, and providing scaffolding to direct signaling. Cytoskeletal components have been implicated in cardiac pathology; however, less attention has been paid to age-related modifications of cardiac cytoskeletal components and how these contribute to dysfunction with increased age. Moreover, significant sex differences in cardiac aging have been identified, but we still lack a complete understanding to the mechanisms behind these differences. This review summarizes what is known about how key cardiomyocyte cytoskeletal components are modified because of age, as well as reported sex-specific differences. Thorough consideration of both age and sex as integral players in cytoskeletal function may reveal potential avenues for more personalized therapeutics.

Coronavirus and the Cytoskeleton of Virus-Infected Cells.

The cytoskeleton, which includes actin filaments, microtubules, and intermediate filaments, is one of the most important networks in the cell and undertakes many fundamental life activities. Among them, actin filaments are mainly responsible for maintaining cell shape and mediating cell movement, microtubules are in charge of coordinating all cargo transport within the cell, and intermediate filaments are mainly thought to guard against external mechanical pressure. In addition to this, cytoskeleton networks are also found to play an essential role in multiple viral infections. Due to the COVID-19 epidemic, including SARS-CoV-2, SARS-CoV and MERS-CoV, so many variants have caused wide public concern, that any virus infection can potentially bring great harm to human beings and society. Therefore, it is of great importance to study coronavirus infection and develop antiviral drugs and vaccines. In this chapter, we summarize in detail how the cytoskeleton responds and participates in coronavirus infection by analyzing the possibility of the cytoskeleton and its related proteins as antiviral targets, thereby providing ideas for finding more effective treatments.

Intermediate filaments in the heart: The dynamic duo of desmin and lamins orchestrates mechanical force transmission.

The intermediate filament (IF) cytoskeleton supports cellular structural integrity, particularly in response to mechanical stress. The most abundant IF proteins in mature cardiomyocytes are desmin and lamins. The desmin network tethers the contractile apparatus and organelles to the nuclear envelope and the sarcolemma, while lamins, as components of the nuclear lamina, provide structural stability to the nucleus and the genome. Mutations in desmin or A-type lamins typically result in cardiomyopathies and recent studies emphasized the synergistic roles of desmin and lamins in the maintenance of nuclear integrity in cardiac myocytes. Here we explore the emerging roles of the interdependent relationship between desmin and lamins in providing resilience to nuclear structure while transducing extracellular mechanical cues into the nucleus.

Posttranslational modifications of keratins and their associated proteins as therapeutic targets in keratin diseases.

The keratin cytoskeleton protects epithelia against mechanical, nonmechanical, and physical stresses, and participates in multiple signaling pathways that regulate cell integrity and resilience. Keratin gene mutations cause multiple rare monoallelic epithelial diseases termed keratinopathies, including the skin diseases Epidermolysis Bullosa Simplex (EBS) and Pachyonychia Congenita (PC), with limited available therapies. The disease-related keratin mutations trigger posttranslational modifications (PTMs) in keratins and their associated proteins that can aggravate the disease. Recent findings of drug high-throughput screening have led to the identification of compounds that may be repurposed, since they are used for other human diseases, to treat keratinopathies. These drugs target unique PTM pathways and sites, including phosphorylation and acetylation of keratins and their associated proteins, and have shed insights into keratin regulation and interactions. They also offer the prospect of testing the use of drug mixtures, with the long view of possible beneficial human use coupled with increased efficacy and lower side effects.

Scaffold, mechanics and functions of nuclear lamins.

Nuclear lamins are type-V intermediate filaments that are involved in many nuclear processes. In mammals, A- and B-type lamins assemble into separate physical meshwork underneath the inner nuclear membrane, the nuclear lamina, with some residual fraction localized within the nucleoplasm. Lamins are the major part of the nucleoskeleton, providing mechanical strength and flexibility to protect the genome and allow nuclear deformability, while also contributing to gene regulation via interactions with chromatin. While lamins are the evolutionary ancestors of all intermediate filament family proteins, their ultimate filamentous assembly is markedly different from their cytoplasmic counterparts. Interestingly, hundreds of genetic mutations in the lamina proteins have been causally linked with a broad range of human pathologies, termed laminopathies. These include muscular, neurological and metabolic disorders, as well as premature aging diseases. Recent technological advances have contributed to resolving the filamentous structure of lamins and the corresponding lamina organization. In this review, we revisit the multiscale lamin organization and discuss its implications on nuclear mechanics and chromatin organization within lamina-associated domains.

Accuracy of serum neurofilament light to identify contrast-enhancing lesions in multiple sclerosis.

BACKGROUND: Contrast-enhancing magnetic resonance imaging (MRI) lesions (CELs) indicate acute multiple sclerosis inflammation. Serum biomarkers, neurofilament light (sNfL), and glial fibrillary acidic protein (sGFAP) may increase in the presence of CELs, and indicate a need to perform MRI. OBJECTIVE: We assessed the accuracy of biomarkers to detect CELs. METHODS: Patients with two gadolinium-enhanced MRIs and serum biomarkers tested within 3 months were included (N = 557, 66% female). Optimal cut-points from Bland-Altman analysis for spot biomarker level and Youden's index for delta-change from remission were evaluated. RESULTS: A total of 116 patients (21%) had CELs. A spot sNfL measurement >23.0 pg/mL corresponded to 7.0 times higher odds of CEL presence (95% CI: 3.8, 12.8), with 25.9% sensitivity, 95.2% specificity, operating characteristic curve (AUC) 0.61; while sNfL delta-change >30.8% from remission corresponded to 5.0 times higher odds (95% CI: 3.2, 7.8), 52.6% sensitivity, 81.9% specificity, AUC 0.67. sGFAP had poor CEL detection. In patients > 50 years, neither cut-point remained significant. sNfL delta-change outperformed spot levels at identifying asymptomatic CELs (AUC 0.67 vs 0.59) and in patients without treatment escalation between samples (AUC 0.67 vs 0.57). CONCLUSION: Spot sNfL >23.0 pg/mL or a 30.8% increase from remission provides modest prediction of CELs in patients <50 years; however, low sNfL does not obviate the need for MRI.

A consumer cross-over trial suggests that there are significant seasonal changes of the tensile properties (wet) of human hair.

OBJECTIVES: Through the cooperation with an industrial partner, we gained a set of data for the tensile properties (wet) of human hair. The hair samples originated from a cross-over study with two groups of individuals, using for a topical application sequentially two products (A and B). Each phase of the study lasted 6 months. The phases of the study by chance covered first largely the winter and then the summer period. Initially, tensile variables were chosen, which not only reflect the mechanical properties of hair (modulus, break strain, and break stress) but which are also considered to have a good connection to practice-relevant hair properties. The initial analysis of the data showed that changes were observed for the variables due to the treatment phases. However, these were either small or difficult to interpret. METHODS: Against this background and using two-factor analysis of variance, we investigated the hypothesis that the tensile properties of hair (wet) may show significant seasonal changes. For this, we chose those two independent variables, which reflect the properties of the intermediate filaments (modulus) and the matrix (break strain) in the composite structure of the hair cortex. RESULTS: The results support the 'seasonal' hypothesis and clearly show that the variables show significant changes from Winter to Summer (modulus: 10% increase; break strain: 3% decrease). The seasonal effect was thus a major reason, why the first stage of the analysis of the data was inconclusive. CONCLUSIONS: The tensile properties of the main morphological components of the cortex show distinct seasonal changes. Towards the summer, the hair becomes stiffer and more brittle. Furthermore, the results suggest that seasonal effects may need to be taken into account when conducting studies on lengths of hair grown during different seasons.

OBJECTIFS: Grâce à la coopération avec un partenaire industriel, nous avons obtenu un ensemble de données sur les propriétés de traction des cheveux (humides) humains. Les échantillons de cheveux provenaient d'une étude croisée avec deux groupes de personnes, utilisant pour une application topique deux produits (A et B) de manière séquentielle. Chaque phase de l'étude a duré 6 mois. Les phases de l'étude ont principalement couvert l'hiver, puis l'été. Initialement les variables de traction ont été choisies reflètent non seulement les propriétés mécaniques des cheveux (modulus, extension de rupture et stress de rupture), mais sont également considérées comme ayant un lien étroit avec les propriétés pertinentes des cheveux. L'analyse initiale des données a montré que des changements ont été observés pour les variables en raison des phases de traitement. Cependant, ils étaient faibles ou difficiles à interpréter. MÉTHODES: Dans ce contexte et à l'aide d'une analyse de variance à deux facteurs, nous avons étudié l'hypothèse selon laquelle les propriétés de traction des cheveux (humides) pourraient montrer des changements saisonniers significatifs. Pour cela, nous avons choisi ces deux variables indépendantes, qui reflètent les propriétés des filaments intermédiaires (modulus) et de la matrice (extension de rupture) dans la structure composite du cortex capillaire. RÉSULTATS: Les résultats appuient l'hypothèse « saisonnière ¼ et indiquent clairement que les variables montrent des évolutions significatives de l'hiver à l'été (modulus : augmentation de 10 % ; extension de rupture : diminution de 3 %). L'effet saisonnier était donc une raison majeure pour laquelle la première étape de l'analyse des données n'a pas été concluante. CONCLUSIONS: Les propriétés de traction des principaux composants morphologiques du cortex montrent des changements saisonniers distincts. Vers l'été, les cheveux deviennent plus raides et plus cassants. En outre, les résultats indiquent que les effets saisonniers devrait être pris en compte lors de la réalisation d'études sur les longueurs des cheveux ayant poussé à différentes saisons.

Woven bone formation and mineralization by rat mesenchymal stromal cells imply increased expression of the intermediate filament desmin.

Background: Disordered and hypomineralized woven bone formation by dysfunctional mesenchymal stromal cells (MSCs) characterize delayed fracture healing and endocrine -metabolic bone disorders like fibrous dysplasia and Paget disease of bone. To shed light on molecular players in osteoblast differentiation, woven bone formation, and mineralization by MSCs we looked at the intermediate filament desmin (DES) during the skeletogenic commitment of rat bone marrow MSCs (rBMSCs), where its bone-related action remains elusive. Results: Monolayer cultures of immunophenotypically- and morphologically - characterized, adult male rBMSCs showed co-localization of desmin (DES) with vimentin, F-actin, and runx2 in all cell morphotypes, each contributing to sparse and dense colonies. Proteomic analysis of these cells revealed a topologically-relevant interactome, focused on cytoskeletal and related enzymes//chaperone/signalling molecules linking DES to runx2 and alkaline phosphatase (ALP). Osteogenic differentiation led to mineralized woven bone nodules confined to dense colonies, significantly smaller and more circular with respect to controls. It significantly increased also colony-forming efficiency and the number of DES-immunoreactive dense colonies, and immunostaining of co-localized DES/runx-2 and DES/ALP. These data confirmed pre-osteoblastic and osteoblastic differentiation, woven bone formation, and mineralization, supporting DES as a player in the molecular pathway leading to the osteogenic fate of rBMSCs. Conclusion: Immunocytochemical and morphometric studies coupled with proteomic and bioinformatic analysis support the concept that DES may act as an upstream signal for the skeletogenic commitment of rBMSCs. Thus, we suggest that altered metabolism of osteoblasts, woven bone, and mineralization by dysfunctional BMSCs might early be revealed by changes in DES expression//levels. Non-union fractures and endocrine - metabolic bone disorders like fibrous dysplasia and Paget disease of bone might take advantage of this molecular evidence for their early diagnosis and follow-up.

Vimentin at the core of wound healing.

As a member of the large family of intermediate filaments (IFs), vimentin has emerged as a highly dynamic and versatile cytoskeletal protein involved in many key processes of wound healing. It is well established that vimentin is involved in epithelial-mesenchymal transition (EMT) during wound healing and metastasis, during which epithelial cells acquire more dynamic and motile characteristics. Moreover, vimentin participates in multiple cellular activities supporting growth, proliferation, migration, cell survival, and stress resilience. Here, we explore the role of vimentin at each phase of wound healing, with focus on how it integrates different signaling pathways and protects cells in the fluctuating and challenging environments that characterize a healing tissue.

Desmin Reorganization by Stimuli Inducing Oxidative Stress and Electrophiles: Role of Its Single Cysteine Residue.

The type III intermediate filament proteins vimentin and GFAP are modulated by oxidants and electrophiles, mainly through perturbation of their single cysteine residues. Desmin, the type III intermediate filament protein specific to muscle cells, is critical for muscle homeostasis, playing a key role in sarcomere organization and mitochondrial function. Here, we have studied the impact of oxidants and cysteine-reactive agents on desmin behavior. Our results show that several reactive species and drugs induce covalent modifications of desmin in vitro, of which its single cysteine residue, C333, is an important target. Moreover, stimuli eliciting oxidative stress or lipoxidation, including H2O2, 15-deoxy-prostaglandin J2, and CoCl2-elicited chemical hypoxia, provoke desmin disorganization in H9c2 rat cardiomyoblasts transfected with wild-type desmin, which is partially attenuated in cells expressing a C333S mutant. Notably, in cells lacking other cytoplasmic intermediate filaments, network formation by desmin C333S appears less efficient than that of desmin wt, especially when these proteins are expressed as fluorescent fusion constructs. Nevertheless, in these cells, the desmin C333S organization is also protected from disruption by oxidants. Taken together, our results indicate that desmin is a target for oxidative and electrophilic stress, which elicit desmin remodeling conditioned by the presence of its single cysteine residue.

RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress.

Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Subsequent return to homeostasis involves clearance of the ERQC by endolysosomes. However, the factors that control perinuclear ER integrity and dynamics remain unclear. Here, we identify vimentin intermediate filaments as perinuclear anchors for the ER and endolysosomes. We show that perinuclear vimentin filaments engage the ER-embedded RING finger protein 26 (RNF26) at the C-terminus of its RING domain. This restricts RNF26 to perinuclear ER subdomains and enables the corresponding spatial retention of endolysosomes through RNF26-mediated membrane contact sites (MCS). We find that both RNF26 and vimentin are required for the perinuclear coalescence of the ERQC and its juxtaposition with proteolytic compartments, which facilitates efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway. Collectively, our findings reveal a scaffolding mechanism that underpins the spatiotemporal integration of organelles during cellular proteostasis.

Uncovering the role of cytoskeleton proteins in the formation of neutrophil extracellular traps.

Neutrophils are a type of lymphocyte involved in innate immune defense. In response to specific stimuli, these phagocytic cells undergo a unique form of cell death, NETosis, during which they release neutrophil extracellular traps (NETs) composed of modified chromatin structures decorated with cytoplasmic and granular proteins. Multiple proteins and pathways have been implicated in the formation of NETs. The cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins, plays a crucial role in resisting deformation, transporting intracellular cargo, and changing shape during movement of eukaryotic cells. It may also have evolved to defend eukaryotic organisms against infection. Recent research focuses on understanding the mechanisms underlying NETs formation and how cytoskeletal networks contribute to this process, by identifying enzymes that trigger NETosis or interact with NETs and influence cellular behavior through cytoskeletal dynamics. An enhanced understanding of the complex relationship between the cytoskeleton and NET formation will provide a framework for future research and the development of targeted therapeutic strategies, and supports the notion that the long-lived cytoskeleton structures may have a lasting impact on this area of research.

Vimentin: from a cytoskeletal protein to a critical modulator of immune response and a target for infection.

Vimentin is an intermediate filament protein that plays a role in cell processes, including cell migration, cell shape and plasticity, or organelle anchorage. However, studies from over the last quarter-century revealed that vimentin can be expressed at the cell surface and even secreted and that its implications in cell physiology largely exceed structural and cytoskeletal functions. Consequently, vimentin contributes to several pathophysiological conditions such as cancer, autoimmune and inflammatory diseases, or infection. In this review, we aimed at covering these various roles and highlighting vimentin implications in the immune response. We also provide an overview of how some microbes including bacteria and viruses have acquired the ability to circumvent vimentin functions in order to interfere with host responses and promote their uptake, persistence, and egress from host cells. Lastly, we discuss the therapeutic approaches associated with vimentin targeting, leading to several beneficial effects such as preventing infection, limiting inflammatory responses, or the progression of cancerous events.

Protein biomarkers in multiple sclerosis.

This review aimed to elucidate protein biomarkers in body fluids, such as blood and cerebrospinal fluid (CSF), to identify those that may be used for early diagnosis of multiple sclerosis (MS), prediction of disease activity, and monitoring of treatment response among MS patients. The potential biomarkers elucidated in this review include neurofilament proteins (NFs), glial fibrillary acidic protein (GFAP), leptin, brain-derived neurotrophic factor (BDNF), chitinase-3-like protein 1 (CHI3L1), C-X-C motif chemokine 13 (CXCL13), and osteopontin (OPN), with each biomarker playing a different role in MS. GFAP, leptin, and CHI3L1 levels were increased in MS patient groups compared to the control group. NFs are the most studied proteins in the MS field, and significant correlations with disease activity, future progression, and treatment outcomes are evident. GFAP CSF level shows a different pattern by MS subtype. Increased concentration of CHI3L1 in the blood/CSF of clinically isolated syndrome (CIS) is an independent predictive factor of conversion to definite MS. BDNF may be affected by chronic progression of MS. CHI3L1 has potential as a biomarker for early diagnosis of MS and prediction of disability progression, while CXCL13 has potential as a biomarker of prognosis of CIS and reflects MS disease activity. OPN was an indicator of disease severity. A periodic detailed patient evaluation should be performed for MS patients, and broadly and easily accessible biomarkers with higher sensitivity and specificity in clinical settings should be identified.