Intermediate filaments

It is likely that future studies involving a molecular biology approach, similar to those described in [7,27,28], will yield fruitful information regarding properties and cellular roles of IF. At this point, our knowledge of the properties and expression of IF remains in stark contrast to our lack of understanding of their biological functions. As pointed out by Franke et al. [29], several lines of investigation have suggested that IF do not serve a general cellular function (i.e. 'housekeeping duties'). Instead, the roles of IF and their constituent proteins are probably related to specific functions of the differentiated cell. Our search for these specific roles will be difficult, but exciting. In the meantime, it is rewarding that IF typing of cells and tumors has already yielded practical information useful in histology and cytology [30].     

Intermediate filaments in cardiomyopathy

Intermediate filament (IF) proteins are critical regulators in health and disease. The discovery of hundreds of mutations in IF genes and posttranslational modifications has been linked to a plethora of human diseases, including, among others, cardiomyopathies, muscular dystrophies, progeria, blistering diseases of the epidermis, and neurodegenerative diseases. The major IF proteins that have been linked to cardiomyopathies and heart failure are the muscle-specific cytoskeletal IF protein desmin and the nuclear IF protein lamin, as a subgroup of the known desminopathies and laminopathies, respectively. The studies so far, both with healthy and diseased heart, have demonstrated the importance of these IF protein networks in intracellular and intercellular integration of structure and function, mechanotransduction and gene activation, cardiomyocyte differentiation and survival, mitochondrial homeostasis, and regulation of metabolism. The high coordination of all these processes is obviously of great importance for the maintenance of proper, life-lasting, and continuous contraction of this highly organized cardiac striated muscle and consequently a healthy heart. In this review, we will cover most known information on the role of IFs in the above processes and how their deficiency or disruption leads to cardiomyopathy and heart failure.     

Intermediate filaments in smooth muscle

The intermediate filament (IF) network is one of the three cytoskeletal systems in smooth muscle. The type III IF proteins vimentin and desmin are major constituents of the network in smooth muscle cells and tissues. Lack of vimentin or desmin impairs contractile ability of various smooth muscle preparations, implying their important role for smooth muscle force development. The IF framework has long been viewed as a fixed cytostructure that solely provides mechanical integrity for the cell. However, recent studies suggest that the IF cytoskeleton is dynamic in mammalian cells in response to various external stimulation. In this review, the structure and biological properties of IF proteins in smooth muscle are summarized. The role of IF proteins in the modulation of smooth muscle force development and redistribution/translocation of signaling partners (such as p130 Crk-associated substrate, CAS) is depicted. This review also summarizes our latest understanding on how the IF network may be regulated in smooth muscle. cytoskeleton; force development; vimentin; desmin     

Intermediate filaments and stress

Before we can explain why so many closely related intermediate filament genes have evolved in vertebrates, while maintaining such dramatically tissue specific expression, we need to understand their function. The best evidence for intermediate filament function comes from observing the consequences of mutation and mis-expression, primarily in human tissues. Mostly these observations suggest that intermediate filaments are important in allowing individual cells, the tissues and whole organs to cope with various types of stress, in health and disease. Exactly how they do this is unclear and many aspects of cell dysfunction have been associated with intermediate filaments to date. In particular, it is still not clear whether the non-mechanical functions now being attributed to intermediate filaments are primary functions of these structural proteins, or secondary consequences of their function to respond to mechanical stress. We discuss selected situations in which responses to stress are clearly influenced by intermediate filaments.     

Intermediate filaments: vimentin moves in

Vimentin intermediate filaments move bi-directionally along microtubules in the cell. Recent work has identified the microtubule motor cytoplasmic dynein as the missing inward-directed motor that drives this movement.     

Intermediate filaments of the lung

Intermediate filaments (IF), a subfamily of the cytoskeletal filaments, provide structural support to cells. Human diseases related to mutations in IF proteins in which their tissue-specific expression is reflected have been found in a broad range of patients. The properties of identified IF mutants are well-studied in vitro in cultured cells and in vivo using transgenic mice expressing IF mutants. However, the association of IF proteins with diseases of the lung is not fully studied yet. Epithelial cells in normal lung express vimentin and various keratins, and the patterns of their expression are altered depending on the progression of the lung diseases. A growing number of studies performed in alveolar epithelial cells demonstrated IF involvement in disease-related aspects including their usefulness as tumor marker, in epithelial-mesenchymal transition and cell migration. However, the lung disease-associated IF functions in animal models are poorly understood, and IF mutations associated with lung diseases in humans have not been reported. In this review, we summarize recent studies that show the significance of IF proteins in lung epithelial cells. Understanding these aspects is an important prerequisite for further investigations on the role of lung IF in animal models and human lung diseases.     

Intermediate filaments mediate cytoskeletal crosstalk

Intermediate filaments, actin-containing microfilaments and microtubules are the three main cytoskeletal systems of vertebrate and many invertebrate cells. Although these systems are composed of distinctly different proteins, they are in constant and intimate communication with one another. Understanding the molecular basis of this cytoskeletal crosstalk is essential for determining the mechanisms that underlie many cell-biological phenomena. Recent studies have revealed that intermediate filaments and their associated proteins are important components in mediating this crosstalk.     

Intermediate filaments and lipoprotein cholesterol

The ability of cells to utilize cholesterol derived from lipoprotein is important in plasma membrane biosynthesis, steroidogenesis and the regulation of sterol synthesis. While the endocytosis of lipoprotein-derived cholesterol has been well characterized, the subsequent events that mediate its post-lysosomal intracellular transport are not understood. Recent studies have suggested that vimentin-type intermediate filaments may have a role in cholesterol transport. The mechanism by which vimentin filaments affect this process is not known, but future studies promise to provide new insights into both the post-lysosomal transport of cholesterol and the intracellular functions of intermediate filaments.     

Intermediate filaments as effectors of differentiation

After the initial discovery of intermediate filament (IF)–forming proteins in 1968, a decade would elapse before they were revealed to comprise a diverse group of proteins which undergo tissue-, developmental stage-, differentiation-, and context-dependent regulation. Our appreciation for just how large (n = 70), conserved, complex, and dynamic IF genes and proteins are became even sharper upon completion of the human genome project. While there has been extraordinary progress in understanding the multimodal roles of IFs in cells and tissues, even revealing them as direct causative agents in a broad array of human genetic disorders, the link between individual IFs and cell differentiation has remained elusive. Here, we review evidence that demonstrates a role for IFs in lineage determination, cell differentiation, and tissue homeostasis. A major theme in this review is the function of IFs as sensors and transducers of mechanical forces, intersecting microenvironmental cues and fundamental processes through cellular redox balance.     

Intermediate filaments regulate astrocyte motility.

Intermediate filaments (IFs) compose, together with actin filaments and microtubules, the cytoskeleton and they exhibit a remarkable but still enigmatic cell-type specificity. In a number of cell types, IFs seem to be instrumental in the maintenance of the mechanical integrity of cells and tissues. The function of IFs in astrocytes has so far remained elusive. We have recently reported that glial scar formation following brain or spinal cord injury is impaired in mice deficient in glial fibrillary acidic protein and vimentin. These mice lack IFs in reactive astrocytes that are normally pivotal in the wound repair process. Here we show that reactive astrocytes devoid of IFs exhibit clear morphological changes and profound defects in cell motility thereby revealing a novel function for IFs.     

Intermediate filaments: a historical perspective

Intracellular protein filaments intermediate in size between actin microfilaments and microtubules are composed of a surprising variety of tissue specific proteins commonly interconnected with other filamentous systems for mechanical stability and decorated by a variety of proteins that provide specialized functions. The sequence conservation of the coiled-coil, alpha-helical structure responsible for polymerization into individual 10 nm filaments defines the classification of intermediate filament proteins into a large gene family. Individual filaments further assemble into bundles and branched cytoskeletons visible in the light microscope. However, it is the diversity of the variable terminal domains that likely contributes most to different functions. The search for the functions of intermediate filament proteins has led to discoveries of roles in diseases of the skin, heart, muscle, liver, brain, adipose tissues and even premature aging. The diversity of uses of intermediate filaments as structural elements and scaffolds for organizing the distribution of decorating molecules contrasts with other cytoskeletal elements. This review is an attempt to provide some recollection of how such a diverse field emerged and changed over about 30 years.     

Intermediate filaments: a role in epithelial polarity

Intermediate filaments have long been considered mechanical components of the cell that provide resistance to deformation stress. Practical experimental problems, including insolubility, lack of good pharmacological antagonists, and the paucity of powerful genetic models have handicapped the research of other functions. In single-layered epithelial cells, keratin intermediate filaments are cortical, either apically polarized or apico-lateral. This review analyzes phenotypes of genetic manipulations of simple epithelial cell keratins in mice and Caenorhabditis elegans that strongly suggest a role of keratins in apico-basal polarization and membrane traffic. Published evidence that intermediate filaments can act as scaffolds for proteins involved in membrane traffic and signaling is also discussed. Such a scaffolding function would generate a highly polarized compartment within the cytoplasm of simple epithelial cells. While in most cases mechanistic explanations for the keratin-null or overexpression phenotypes are still missing, it is hoped that investigators will be encouraged to study these as yet poorly understood functions of intermediate filaments.