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Viruses Feb 2023Microfilaments and microtubules, two crucial structures of cytoskeletal networks, are usurped by various viruses for their entry, egress, and/or intracellular...
Microfilaments and microtubules, two crucial structures of cytoskeletal networks, are usurped by various viruses for their entry, egress, and/or intracellular trafficking, including the Rabies virus (RABV). Intermediate filaments (IFs) are the third major component of cytoskeletal filaments; however, little is known about the role of IFs during the RABV infection. Here, we identified the IF protein desmin as a novel host interactor with the RABV matrix protein, and we show that this physical interaction has a functional impact on the virus lifecycle. We found that the overexpression of desmin facilitates the RABV infection by increasing the progeny virus yield, and the suppression of endogenous desmin inhibits virus replication. Furthermore, we used confocal microscopy to observe that the RABV-M co-localizes with desmin in IF bundles in the BHK-21 cells. Lastly, we found that mice challenged with RABV displayed an enhanced expression of desmin in the brains of infected animals. These findings reveal a desmin/RABV-M interaction that positively regulates the virus infection and suggests that the RABV may utilize cellular IFs as tracks for the intracellular transport of viral components and efficient budding.
Topics: Animals; Mice; Desmin; Rabies; Rabies virus; Cytoskeleton; Intermediate Filaments; Viral Matrix Proteins
PubMed: 36851648
DOI: 10.3390/v15020434 -
International Journal of Biological... 2023Elastic cartilage tissue engineering is promising for providing available scaffolds for plastic reconstructive surgery. The insufficient mechanical strength of...
Elastic cartilage tissue engineering is promising for providing available scaffolds for plastic reconstructive surgery. The insufficient mechanical strength of regenerative tissue and scarce resources of reparative cells are two obstacles for the preparation of tissue-engineered elastic cartilage scaffolds. Auricular chondrocytes are important reparative cells for elastic cartilage tissue engineering, but resources are scarce. Identifying auricular chondrocytes with enhanced capability of elastic cartilage formation is conducive to reducing the damage to donor sites by decreasing the demand on native tissue isolation. Based on the biochemical and biomechanical differences in native auricular cartilage, we found that auricular chondrocytes with upregulated desmin expressed more integrin β1, forming a stronger interaction with the substrate. Meanwhile, activated MAPK pathway was found in auricular chondrocytes highly expressing desmin. When desmin was knocked down, the chondrogenesis and mechanical sensitivity of chondrocytes were both impaired, and the MAPK pathway was downregulated. Finally, auricular chondrocytes highly expressing desmin regenerated more elastic cartilage with increased ECM mechanical strength. Therefore, desmin/integrin β1/MAPK signaling can not only serve as a selection standard but also a manipulation target of auricular chondrocytes to promote elastic cartilage regeneration.
Topics: Elastic Cartilage; Integrin beta1; Desmin; Chondrocytes; Tissue Engineering; Tissue Scaffolds; Cells, Cultured
PubMed: 37324935
DOI: 10.7150/ijbs.83024 -
American Journal of Physiology. Cell... May 2019Mitochondria perform a central role in life and death of the eukaryotic cell. They are major players in the generation of macroergic compounds and function as integrated... (Review)
Review
Mitochondria perform a central role in life and death of the eukaryotic cell. They are major players in the generation of macroergic compounds and function as integrated signaling pathways, including the regulation of Ca signals and apoptosis. A growing amount of evidence is demonstrating that mitochondria of muscle cells use cytoskeletal proteins (both microtubules and intermediate filaments) not only for their movement and proper cellular positioning, but also to maintain their biogenesis, morphology, function, and regulation of energy fluxes through the outer mitochondrial membrane (MOM). Here we consider the known literature data concerning the role of tubulin, plectin, desmin and vimentin in bioenergetic function of mitochondria in striated muscle cells, as well as in controlling the permeability of MOM for adenine nucleotides (ADNs). This is of great interest since dysfunctionality of these cytoskeletal proteins has been shown to result in severe myopathy associated with pronounced mitochondrial dysfunction. Further efforts are needed to uncover the pathways by which the cytoskeleton supports the functional capacity of mitochondria and transport of ADN(s) across the MOM (through voltage-dependent anion channel).
Topics: Animals; Desmin; Humans; Mitochondria; Mitochondrial Membranes; Muscle Cells; Plectin; Tubulin; Vimentin
PubMed: 30811221
DOI: 10.1152/ajpcell.00303.2018 -
What does desmin do: A bibliometric assessment of the functions of the muscle intermediate filament.Experimental Biology and Medicine... Apr 2022Intermediate filaments were first described in muscle in 1968, and desmin was biochemically identified about 10 years afterwards. Its importance grew after the...
Intermediate filaments were first described in muscle in 1968, and desmin was biochemically identified about 10 years afterwards. Its importance grew after the identification of desminopathies and desmin mutations that cause mostly cardiopathies. Since its characterization until recently, different functions have been attributed to desmin. Here, we use bibliometric tools to evaluate the articles published about desmin and to assess its several putative functions. We identified the most productive authors and the relationships between research groups. We studied the more frequent words among 9734 articles (September 2021) containing "desmin" on the title and abstract, to identify the major research focus. We generated an interactive spreadsheet with the 934 papers that contain "desmin" only on the title that can be used to search and quantify terms in the abstract. We further selected the articles that contained the terms "function" or "role" from the spreadsheet, which we then classified according to type of function, organelle, or tissue involved. Based on the bibliographic analysis, we assess comparatively the putative functions, and we propose an alternative explanation for the desmin function.
Topics: Cytoskeleton; Desmin; Intermediate Filaments; Muscles; Mutation
PubMed: 35130760
DOI: 10.1177/15353702221075035 -
American Journal of Physiology. Cell... Aug 2020Skeletal muscle is a target of contraction-induced loading (CiL), leading to protein unfolding or cellular perturbations, respectively. While cytoskeletal desmin is...
Skeletal muscle is a target of contraction-induced loading (CiL), leading to protein unfolding or cellular perturbations, respectively. While cytoskeletal desmin is responsible for ongoing structural stabilization, in the immediate response to CiL, alpha-crystallin B (CRYAB) is phosphorylated at serine 59 (CRYAB) by P38, acutely protecting the cytoskeleton. To reveal adaptation and deadaptation of these myofibrillar subsystems to CiL, we examined CRYAB, P38, and desmin regulation following resistance exercise at diverse time points of a chronic training period. Mechanosensitive JNK phosphorylation (JNK) was determined to indicate the presence of mechanical components in CiL. Within 6 wk, subjects performed 13 resistance exercise bouts at the 8-12 repetition maximum, followed by 10 days detraining and a final 14th bout. Biopsies were taken at baseline and after the 1st, 3rd, 7th, 10th, 13th, and 14th bout. To assess whether potential desensitization to CiL can be mitigated, one group trained with progressive and a second with constant loading. As no group differences were found, all subjects were combined for statistics. Total and phosphorylated P38 was not regulated over the time course. CRYAB and JNK strongly increased following the unaccustomed first bout. This exercise-induced CRYAB/JNK increase disappeared with the 10th until 13th bout. As response to the detraining period, the 14th bout led to a renewed increase in CRYAB. Desmin content followed CRYAB inversely, i.e., was up- when CRYAB was downregulated and vice versa. In conclusion, the CRYAB response indicates increase and decrease in resistance to CiL, in which a reinforced desmin network could play an essential role by structurally stabilizing the cells.
Topics: Adaptation, Physiological; Adult; Cytoskeleton; Desmin; Gene Expression Regulation; Humans; Male; Muscle Contraction; Muscle, Skeletal; Phosphorylation; Resistance Training; Young Adult; alpha-Crystallin B Chain
PubMed: 32520607
DOI: 10.1152/ajpcell.00087.2020 -
Differentiation; Research in Biological... Sep 2007Desmin contributes to structural integrity and function of the myocardium but its function seems to be redundant in early cardiomyogenesis in the desmin null mouse...
Desmin contributes to structural integrity and function of the myocardium but its function seems to be redundant in early cardiomyogenesis in the desmin null mouse model. To test the hypothesis that desmin also plays a supportive role in cardiomyogenic commitment and early differentiation of cardiomyocytes we investigated cardiomyogenesis in embryoid bodies expressing different desmin alleles. Constitutive expression of desmin and increased synthesis during mesoderm formation led to the up-regulation of brachyury and nkx2.5 genes, accelerated early cardiomyogenesis and resulted in the development of large, proliferating, highly interconnected, and synchronously beating cardiomyocyte clusters, whereas desmin null cardiomyocytes featured an opposite phenotype. In contrast, constitutive expression of amino-terminally truncated desmin(Delta1-48) interfered with the beginning of cardiomyogenesis, caused down-regulation of mesodermal and myocardial transcription factors, and hampered myofibrillogenesis and survival of cardiomyocytes. These results provide first evidence that a type III intermediate filament protein takes part in regulating the differentiation of mesoderm to cardiomyocytes at the very beginning of cardiomyogenesis.
Topics: Animals; Cell Aggregation; Cell Differentiation; Cell Line; Desmin; Fetal Proteins; Homeobox Protein Nkx-2.5; Homeodomain Proteins; Mesoderm; Mice; Mice, Knockout; Myocytes, Cardiac; T-Box Domain Proteins; Transcription Factors; Up-Regulation
PubMed: 17381547
DOI: 10.1111/j.1432-0436.2007.00162.x -
The Journal of Clinical Investigation Jan 2011Muscle contraction relies on a highly organized intracellular network of membrane organelles and cytoskeleton proteins. Among the latter are the intermediate filaments...
Muscle contraction relies on a highly organized intracellular network of membrane organelles and cytoskeleton proteins. Among the latter are the intermediate filaments (IFs), a large family of proteins mutated in more than 30 human diseases. For example, mutations in the DES gene, which encodes the IF desmin, lead to desmin-related myopathy and cardiomyopathy. Here, we demonstrate that myotubularin (MTM1), which is mutated in individuals with X-linked centronuclear myopathy (XLCNM; also known as myotubular myopathy), is a desmin-binding protein and provide evidence for direct regulation of desmin by MTM1 in vitro and in vivo. XLCNM-causing mutations in MTM1 disrupted the MTM1-desmin complex, resulting in abnormal IF assembly and architecture in muscle cells and both mouse and human skeletal muscles. Adeno-associated virus-mediated ectopic expression of WT MTM1 in Mtm1-KO muscle reestablished normal desmin expression and localization. In addition, decreased MTM1 expression and XLCNM-causing mutations induced abnormal mitochondrial positioning, shape, dynamics, and function. We therefore conclude that MTM1 is a major regulator of both the desmin cytoskeleton and mitochondria homeostasis, specifically in skeletal muscle. Defects in IF stabilization and mitochondrial dynamics appear as common physiopathological features of centronuclear myopathies and desmin-related myopathies.
Topics: Animals; Cell Line; Desmin; Humans; In Vitro Techniques; Intermediate Filaments; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondria, Muscle; Models, Molecular; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Protein Interaction Domains and Motifs; Protein Tyrosine Phosphatases, Non-Receptor; Recombinant Fusion Proteins
PubMed: 21135508
DOI: 10.1172/JCI44021 -
JCI Insight Sep 2021Stromal interaction molecule 1 (STIM1), the sarcoplasmic reticulum (SR) transmembrane protein, activates store-operated Ca2+ entry (SOCE) in skeletal muscle and,...
Stromal interaction molecule 1 (STIM1), the sarcoplasmic reticulum (SR) transmembrane protein, activates store-operated Ca2+ entry (SOCE) in skeletal muscle and, thereby, coordinates Ca2+ homeostasis, Ca2+-dependent gene expression, and contractility. STIM1 occupies space in the junctional SR membrane of the triads and the longitudinal SR at the Z-line. How STIM1 is organized and is retained in these specific subdomains of the SR is unclear. Here, we identified desmin, the major type III intermediate filament protein in muscle, as a binding partner for STIM1 based on a yeast 2-hybrid screen. Validation of the desmin-STIM1 interaction by immunoprecipitation and immunolocalization confirmed that the CC1-SOAR domains of STIM1 interact with desmin to enhance STIM1 oligomerization yet limit SOCE. Based on our studies of desmin-KO mice, we developed a model wherein desmin connected STIM1 at the Z-line in order to regulate the efficiency of Ca2+ refilling of the SR. Taken together, these studies showed that desmin-STIM1 assembles a cytoskeletal-SR connection that is important for Ca2+ signaling in skeletal muscle.
Topics: Animals; Calcium Signaling; Cells, Cultured; Desmin; Gene Expression Regulation; Membrane Proteins; Mice; Microscopy, Electron, Transmission; Models, Animal; Muscle, Skeletal; RNA; Sarcoplasmic Reticulum; Stromal Interaction Molecule 1
PubMed: 34494555
DOI: 10.1172/jci.insight.143472 -
Cancer Medicine Mar 2023Pleural mesothelioma (PM) is typically diagnosed late during the disease. Earlier detection can increase the chance of effective therapy. Recurrent pleural effusions are...
BACKGROUND
Pleural mesothelioma (PM) is typically diagnosed late during the disease. Earlier detection can increase the chance of effective therapy. Recurrent pleural effusions are the earliest symptoms displaying an array of cytomorphological changes from reactive atypia to malignancy. Diagnosis is possible on effusion cytology by applying molecular and immunocytochemical markers, the main difficulty being when to suspect PM and to differentiate PM from metastatic adenocarcinoma and reactive mesothelial proliferations.
METHODS
We evaluated the diagnostic performance of two immunocytochemical dual stains (BerEp4/Calretinin and Desmin/Epithelial Membrane Antigen (EMA)) on 149 ethanol-fixed cytospin preparation as an initial step to solve the mentioned diagnostic difficulty. The immunocytochemical reactivity pattern was evaluated by two independent investigators. The final diagnosis corresponded to PM (n = 20), metastatic adenocarcinoma (n = 83), and mesotheliosis (n = 46) in these cases.
RESULTS
Calretinin had 99% specificity and 98% sensitivity for indicating a mesothelial phenotype, while BerEp4 distinguished the adenocarcinoma cases with 98% specificity and 99% sensitivity. EMA displayed 96% specificity and 99% sensitivity in malignant cases, while Desmin without EMA present showed 99% specificity and 96% sensitivity for indicating benign mesothelial proliferation.
CONCLUSIONS
Interpretation of the four immunoreactions is improved when performed as dual stains. The dual staining is a useful tool in the initial handling of atypical effusions and guides the subsequent choice of antibody panels for more detailed subclassification of malignant effusions.
Topics: Humans; Desmin; Calbindin 2; Mucin-1; Mesothelioma; Mesothelioma, Malignant; Staining and Labeling; Pleural Neoplasms; Adenocarcinoma
PubMed: 36259232
DOI: 10.1002/cam4.5353 -
Circulation Research May 2018Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer and Parkinson diseases. Yet,...
RATIONALE
Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer and Parkinson diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear.
OBJECTIVE
We previously reported a rise in monophosphorylated, aggregate-prone desmin in canine and human HF. We now tested whether monophosphorylated desmin acts as the seed nucleating PAOs formation and determined whether positron emission tomography is able to detect myocardial PAOs in nongenetic HF.
METHODS AND RESULTS
Here, we first show that toxic cardiac PAOs accumulate in the myocardium of mice subjected to transverse aortic constriction and that PAOs comigrate with the cytoskeletal protein desmin in this well-established model of acquired HF. We confirm this evidence in cardiac extracts from human ischemic and nonischemic HF. We also demonstrate that Ser31 phosphorylated desmin aggregates extensively in cultured cardiomyocytes. Lastly, we were able to detect the in vivo accumulation of cardiac PAOs using positron emission tomography for the first time in acquired HF.
CONCLUSIONS
Ser31 phosphorylated desmin is a likely candidate seed for the nucleation process leading to cardiac PAOs deposition. Desmin post-translational processing and misfolding constitute a new, attractive avenue for the diagnosis and treatment of the cardiac accumulation of toxic PAOs that can now be measured by positron emission tomography in acquired HF.
Topics: Amyloid; Animals; Catechin; Cells, Cultured; Desmin; Female; Genetic Vectors; Heart Failure; Humans; Male; Mass Spectrometry; Mice; Mice, Knockout; Mutagenesis, Site-Directed; Myocardial Ischemia; Myocytes, Cardiac; Phosphorylation; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Pressure; Protein Aggregates; Protein Folding; Protein Processing, Post-Translational; Rats; Recombinant Proteins; alpha-Crystallins; beta-Crystallins
PubMed: 29483093
DOI: 10.1161/CIRCRESAHA.117.312082