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American Journal of Physiology. Cell... Apr 2020This review analyzes data concerning patients with cardiomyopathies or skeletal myopathies associated with a variation in the intermediate filament (IF) synemin gene (),... (Review)
Review
This review analyzes data concerning patients with cardiomyopathies or skeletal myopathies associated with a variation in the intermediate filament (IF) synemin gene (), also referred to as desmuslin (). Molecular studies demonstrate that synemin copolymerizes with desmin and vimentin IF and interacts with vinculin, α-actinin, α-dystrobrevin, dystrophin, talin, and zyxin. It has been found that synemin is an A-kinase-anchoring protein (AKAP) that anchors protein kinase A (PKA) and modulates the PKA-dependent phosphorylation of several cytoskeletal substrates such as desmin. Because several IF proteins, including desmin, have been implicated in human genetic disorders such as dominant or recessive congenital and adult-onset myopathy, synemin becomes a significant candidate for cardiac and skeletal myopathies of unknown etiology. Because is a new candidate gene that displays numerous sequence polymorphisms, in this review, we summarize the genetic and clinical literature about mutations. Protein-changing variants (missense, frameshifts, nonsense) were further evaluated based on structural modifications and amino acid interactions. We present in silico modeling of helical salt-bridges between residues to evaluate the impact of the synemin networks crucial to interactions with cytoskeletal proteins. Finally, a discussion is featured regarding certain variants that may contribute to the disease state.
Topics: Animals; Cytoskeleton; Heart; Humans; Intermediate Filament Proteins; Intermediate Filaments; Muscle Proteins; Muscular Diseases
PubMed: 32023076
DOI: 10.1152/ajpcell.00485.2019 -
Current Opinion in Cell Biology Dec 2023The dominant structural feature of intermediate filament (IF) proteins is a centrally located α-helix. These long α-helical segments become paired in a parallel... (Review)
Review
The dominant structural feature of intermediate filament (IF) proteins is a centrally located α-helix. These long α-helical segments become paired in a parallel orientation to form coiled-coil dimers. Pairs of dimers further coalesce in an anti-parallel orientation to form tetramers. These early stages of intermediate filament assembly can be accomplished solely by the central α-helices. By contrast, the assembly of tetramers into mature intermediate filaments is reliant upon an N-terminal head domain. IF head domains measure roughly 100 amino acids in length and have long been understood to exist in a state of structural disorder. Here, we describe experiments favoring the unexpected idea that head domains self-associate to form transient structural order in the form of labile cross-β interactions. We propose that this weak form of protein structure allows for dynamic regulation of IF assembly and disassembly. We further offer that what we have learned from studies of IF head domains may represent a simple, unifying template for understanding how thousands of other intrinsically disordered proteins help to establish dynamic morphological order within eukaryotic cells.
Topics: Intermediate Filaments; Intermediate Filament Proteins
PubMed: 37871501
DOI: 10.1016/j.ceb.2023.102262 -
Proceedings of the Japan Academy.... 2019Intermediate filaments (IFs), in coordination with microfilaments and microtubules, form the structural framework of the cytoskeleton and nucleus, thereby providing... (Review)
Review
Intermediate filaments (IFs), in coordination with microfilaments and microtubules, form the structural framework of the cytoskeleton and nucleus, thereby providing mechanical support against cellular stresses and anchoring intracellular organelles in place. The assembly and disassembly of IFs are mainly regulated by the phosphorylation of IF proteins. These phosphorylation states can be tracked using antibodies raised against phosphopeptides in the target proteins. IFs exert their functions through interactions with not only structural proteins, but also non-structural proteins involved in cell signaling, such as stress responses, apoptosis, and cell proliferation. This review highlights findings related to how IFs regulate cell division through phosphorylation cascades and how trichoplein, a centriolar protein originally identified as a keratin-associated protein, regulates the cell cycle through primary cilium formation.
Topics: Animals; Cell Proliferation; Cytoskeletal Proteins; Homeostasis; Humans; Intermediate Filaments; Phosphorylation; Protein Processing, Post-Translational
PubMed: 31611503
DOI: 10.2183/pjab.95.034 -
Cells May 2019Intermediate filament (IF) proteins make up the largest family of cytoskeletal proteins in metazoans, and are traditionally known for their roles in fostering structural... (Review)
Review
Intermediate filament (IF) proteins make up the largest family of cytoskeletal proteins in metazoans, and are traditionally known for their roles in fostering structural integrity in cells and tissues. Remarkably, individual IF genes are tightly regulated in a fashion that reflects the type of tissue, its developmental and differentiation stages, and biological context. In cancer, IF proteins serve as diagnostic markers, as tumor cells partially retain their original signature expression of IF proteins. However, there are also characteristic alterations in IF gene expression and protein regulation. The use of high throughput analytics suggests that tumor-associated alterations in IF gene expression have prognostic value. Parallel research is also showing that IF proteins directly and significantly impact several key cellular properties, including proliferation, death, migration, and invasiveness, with a demonstrated impact on the development, progression, and characteristics of various tumors. In this review, we draw from recent studies focused on three IF proteins most associated with cancer (keratins, vimentin, and nestin) to highlight how several "hallmarks of cancer" described by Hanahan and Weinberg are impacted by IF proteins. The evidence already in hand establishes that IF proteins function beyond their classical roles as markers and serve as effectors of tumorigenesis.
Topics: Animals; Carcinogenesis; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Immunity, Innate; Inflammation; Intermediate Filaments; Keratins; Mice; Neoplasm Metastasis; Neovascularization, Pathologic; Nestin; Vimentin
PubMed: 31126068
DOI: 10.3390/cells8050497 -
Journal of Molecular Cell Biology Jul 2020The emerging coronavirus (CoV) pandemic is threatening the public health all over the world. Cytoskeleton is an intricate network involved in controlling cell shape,... (Review)
Review
The emerging coronavirus (CoV) pandemic is threatening the public health all over the world. Cytoskeleton is an intricate network involved in controlling cell shape, cargo transport, signal transduction, and cell division. Infection biology studies have illuminated essential roles for cytoskeleton in mediating the outcome of host‒virus interactions. In this review, we discuss the dynamic interactions between actin filaments, microtubules, intermediate filaments, and CoVs. In one round of viral life cycle, CoVs surf along filopodia on the host membrane to the entry sites, utilize specific intermediate filament protein as co-receptor to enter target cells, hijack microtubules for transportation to replication and assembly sites, and promote actin filaments polymerization to provide forces for egress. During CoV infection, disruption of host cytoskeleton homeostasis and modification state is tightly connected to pathological processes, such as defective cytokinesis, demyelinating, cilia loss, and neuron necrosis. There are increasing mechanistic studies on cytoskeleton upon CoV infection, such as viral protein‒cytoskeleton interaction, changes in the expression and post-translation modification, related signaling pathways, and incorporation with other host factors. Collectively, these insights provide new concepts for fundamental virology and the control of CoV infection.
Topics: Actin Cytoskeleton; Animals; Biological Transport, Active; Brain; Cilia; Coronavirus; Coronavirus Infections; Cytoskeleton; Host Microbial Interactions; Humans; Intermediate Filaments; Microtubules; Models, Biological; Phylogeny; Receptors, Virus; Signal Transduction; Virus Assembly; Virus Internalization; Virus Replication
PubMed: 32717049
DOI: 10.1093/jmcb/mjaa042 -
Revista de NeurologiaThe aim of this study is to analyse the different types of myopathies that are included under the name of filament pathologies and to review both their clinical,... (Review)
Review
AIMS
The aim of this study is to analyse the different types of myopathies that are included under the name of filament pathologies and to review both their clinical, pathological and genetic aspects.
DEVELOPMENT
The term filament pathologies embraces a heterogeneous group of diseases caused by mutations in the genes that code for the intermediate filaments. Myofibrillar myopathies or myopathies with desmin accumulation belong to the group of filament pathologies. Myofibrillar myopathies are clinically and genetically heterogeneous diseases, with common myopathological bases, which translate a process of myofibril degradation. One characteristic of these diseases is the presence of desmin immunoreactive inclusions in the cytoplasm of the muscle fibres. Approximately a third of the cases are due to mutations in the desmin gene, although to date mutations in the alpha-B-crystallin gene have been reported in two families. In the other patients the gene responsible for the disease remains unknown.
CONCLUSION
The complexity of the so-called 'filament pathologies' calls for a multidisciplinary approach to the patient so that the myopathy can be correctly classified. This should consist in a clinical and neurophysiological examination, an immunohistochemical and electron microscope study of the muscle biopsy, and a genetic analysis to check for mutations in the desmin and the alpha-B-crystallin gene.
Topics: Animals; Desmin; Humans; Intermediate Filaments; Myofibrils; Myopathies, Structural, Congenital; alpha-Crystallin B Chain
PubMed: 14593638
DOI: No ID Found -
Current Opinion in Cell Biology Dec 2023The intermediate filament (IF) cytoskeleton supports cellular structural integrity, particularly in response to mechanical stress. The most abundant IF proteins in... (Review)
Review
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.
Topics: Intermediate Filaments; Lamins; Desmin; Cytoskeleton; Nuclear Lamina
PubMed: 37972529
DOI: 10.1016/j.ceb.2023.102280 -
Biological Chemistry Jul 2023The cytoskeleton of eukaryotes consists of actin filaments, microtubules and intermediate filaments (IF). IFs, in particular, are prone to pronounced phosphorylation,...
The cytoskeleton of eukaryotes consists of actin filaments, microtubules and intermediate filaments (IF). IFs, in particular, are prone to pronounced phosphorylation, leading to additional charges on the affected amino acids. In recent years, a variety of experiments employing either reconstituted protein systems or living cells have revealed that these altered charge patterns form the basis for a number of very diverse cellular functions and processes, including reversible filament assembly, filament softening, network remodeling, cell migration, interactions with other protein structures, and biochemical signaling.
Topics: Intermediate Filaments; Phosphorylation; Vimentin; Cytoskeleton; Actin Cytoskeleton
PubMed: 37074314
DOI: 10.1515/hsz-2023-0140 -
Cells Aug 2021The cytoskeleton of the eukaryotic cell provides a structural and functional scaffold enabling biochemical and cellular functions. While actin and microtubules form the... (Review)
Review
The cytoskeleton of the eukaryotic cell provides a structural and functional scaffold enabling biochemical and cellular functions. While actin and microtubules form the main framework of the cell, intermediate filament networks provide unique mechanical properties that increase the resilience of both the cytoplasm and the nucleus, thereby maintaining cellular function while under mechanical pressure. Intermediate filaments (IFs) are imperative to a plethora of regulatory and signaling functions in mechanotransduction. Mutations in all types of IF proteins are known to affect the architectural integrity and function of cellular processes, leading to debilitating diseases. The basic building block of all IFs are elongated α-helical coiled-coils that assemble hierarchically into complex meshworks. A remarkable mechanical feature of IFs is the capability of coiled-coils to metamorphize into β-sheets under stress, making them one of the strongest and most resilient mechanical entities in nature. Here, we discuss structural and mechanical aspects of IFs with a focus on nuclear lamins and vimentin.
Topics: Actins; Cell Nucleus; Cytoplasm; Cytoskeleton; Humans; Intermediate Filaments; Lamins; Microtubules; Vimentin
PubMed: 34440729
DOI: 10.3390/cells10081960 -
Histochemistry and Cell Biology Jun 2008Intermediate filaments (IFs) represent the largest cytoskeletal gene family comprising approximately 70 genes expressed in tissue specific manner. In addition to... (Review)
Review
Intermediate filaments (IFs) represent the largest cytoskeletal gene family comprising approximately 70 genes expressed in tissue specific manner. In addition to scaffolding function, they form complex signaling platforms and interact with various kinases, adaptor, and apoptotic proteins. IFs are established cytoprotectants and IF variants are associated with >30 human diseases. Furthermore, IF-containing inclusion bodies are characteristic features of several neurodegenerative, muscular, and other disorders. Acidic (type I) and basic keratins (type II) build obligatory type I and type II heteropolymers and are expressed in epithelial cells. Adult hepatocytes contain K8 and K18 as their only cytoplasmic IF pair, whereas cholangiocytes express K7 and K19 in addition. K8/K18-deficient animals exhibit a marked susceptibility to various toxic agents and Fas-induced apoptosis. In humans, K8/K18 variants predispose to development of end-stage liver disease and acute liver failure (ALF). K8/K18 variants also associate with development of liver fibrosis in patients with chronic hepatitis C. Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated K8/K18, chaperones and sequestosome1/p62 (p62) as their major constituents. MDBs are found in various liver diseases including alcoholic and non-alcoholic steatohepatitis and can be formed in mice by feeding hepatotoxic substances griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). MDBs also arise in cell culture after transfection with K8/K18, ubiquitin, and p62. Major factors that determine MDB formation in vivo are the type of stress (with oxidative stress as a major player), the extent of stress-induced protein misfolding and resulting chaperone, proteasome and autophagy overload, keratin 8 excess, transglutaminase activation with transamidation of keratin 8 and p62 upregulation.
Topics: Humans; Inclusion Bodies; Intermediate Filaments; Keratins; Liver; Liver Diseases; Organelles; Protein Isoforms
PubMed: 18443813
DOI: 10.1007/s00418-008-0431-x