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ScienceDirect Editorial overview: Cell architecture: Intermediate filaments — from molecules to patients Elly M Hol and Sandrine Etienne-Manneville Current Opinion in Cell Biology 2015, 32:v–vi For a complete overview see the Issue Available online 6th February 2015 http://dx.doi.org/10.1016/j.ceb.2015.01.007 0955-0674/# 2015 Elsevier Ltd. All rights reserved.

Elly M Hol1,2,3 1

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands 2

Netherlands Institute for Neuroscience – An Institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands 3 Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands

Elly Hol is professor of ‘Glia biology of Brain Diseases’ at the Brain Center Rudolf Magnus of the University Medical Center in Utrecht. She is fascinated by the glial intermediate filament cytoskeleton, and more precisely GFAP. Her research is focused on the functional changes in astrocytes in brain disease and the role of GFAP in this.

Sandrine Etienne-Manneville Institut Pasteur – CNRS UMR 3691, Cell Polarity, Migration and Cancer Unit, 25 rue du Dr Roux, 75724 Paris Cedex 15, France e-mail: [email protected] Sandrine Etienne-Manneville is heading the Cell Polarity, Migration and Cancer Unit and the CNRS Unit ‘Physiological and Pathological Cell Dynamics’ (UMR 3691) at the Institut Pasteur in Paris. Her research focuses on the mechanisms controlling polarization and migration of normal and tumoral astrocytes and in particular in the regulation of cytoskeleton dynamics during these processes.

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From microbes to man for cells to have shape, form and function they need a dynamic, internal skeleton. This skeleton is known as the cytoskeleton which comprises three major filament systems: microfilaments, microtubules, and intermediate filaments. Whereas microfilaments and microtubules serve as tracks for motor proteins and are engaged in cell motility, intermediate filaments are fundamentally engaged in determining cellular plasticity. Intermediate filaments are crucial for the mechanical integrity and biological function of many different tissues in the body. In this issue of Current Opinion in Cell Biology, leaders from the field of intermediate filaments unravel the novel developments in biological, physical, and chemical technology which contribute to our recent increase in knowledge of the nanomechanics and biological function of the intermediate filament cytoskeleton. In sharp contrast with the components of the microtubule and the actin cytoskeleton which are more or less ubiquitously expressed in all cell types, the intermediate filament gene family comprises over 70 members which are introduced here by Peter and Stick. With the exception of the nuclear cytoskeleton formed by the ubiquitously expressed lamins, presented in the review of Gruenbaum and Medalia, intermediate filament proteins are differentially expressed during development and in distinct cell types. In addition, it has recently been shown that splice variants of intermediate filament proteins are expressed, adding a level of complexity to this system. The large variety of intermediate filament proteins form highly specialized polymeric filamentous networks, such as keratins in skin, vimentin in mesenchymal cells, neurofilaments, GFAP, a-internexin and synemin in the central nervous system, desmin and syncoilin in muscle, peripherin in the peripheral nervous system and nestin in neural stem cells. Reviews from Loschke et al., Hol and Pekny and Laser-Azogui et al. describe intermediate filament networks specifically found in epithelial, glial, and neuronal cells and highlight their structural and functional properties. Despite the broad variety of intermediate filament proteins expressed in different tissues, there is a high level of similarity in the structural design of the intermediate filament cytoskeleton. The review by Chernyatina et al. offers an overview of the structure of intermediate filament proteins. The monomers making up the filaments do differ in their amino acid sequence, but share similar protein domain motifs, as they all consist of a central ahelical rod flanked by flexible and highly variable N-termini and C-termini. All intermediate filament proteins form networks following a similar, hierarchical assembly scheme. Intermediate filaments have very attractive Current Opinion in Cell Biology 2015, 32:v–vi

vi Cell architecture

biomechanical properties such as the ability to withstand very large forces via their strain-hardening feature. The component proteins of intermediate filaments make some of the most resilient filaments encountered in biology and are, for instance, the staple component of hair, hoof and skin. The review by Quinlan et al. illustrates how understanding the structure/mechanics relation for different intermediate filament proteins allows the extraction of bio-inspired design principles to build new materials that are stronger than conventional man-made plastics, yet built from renewable, bio-friendly resources (proteins or (synthetic) peptides). As reviewed by Ko¨ster et al. the in vitro mechanical properties of intermediate filaments can be translated to living cells where the intermediate filaments form an extremely resistant network which can be dramatically extended. Intermediate filaments are thus believed to play a key role in protecting cells from excessive deformation. In their review, Wiche et al. highlight the role of versatile cytolinker proteins such as plectin in the interaction of intermediate filaments with cell adhesive structures. By connecting the cell membrane to cellular organelles and to the nucleus, intermediate filaments convey resistance against mechanical stress, thereby preventing structural disintegration of the cell. It is also tailored to transduce mechanical force and biochemical signals into a biological response. Cells in tissue ‘sense’ their environment and respond to external forces, applied in particular through focal adhesions and cell adhesion complexes. The role of intermediate filaments in the signalling to and from such structures is discussed in the reviews by Leube et al. and Osmani and Labouesse. Complex intracellular pathways transmit this information towards the nucleus leading to the launch of transcriptional programmes. The intermediate filament cytoskeleton integrates signalling and transport processes in cells and has emerged as a signalling platform in stress and mitogenic signalling pathways, as well as an organizer of a number of associated proteins (chaperones, molecular motors and kinases). It transduces mechanical and biological stimuli into molecular and then cellular responses such as cell migration. Here, Leduc and Etienne-Manneville debate evidences showing the importance of intermediate filament composition and structure to this complex cellular process. From this example, it is clear that intermediate filaments must act in concert with the other cytoskeletal elements to contribute to a comprehensive cell response. The review by Huber et al. discusses the interplay between intermediate filaments, actin microfilaments, and microtubules. The intermediate filament cytoskeleton is regarded as a main candidate for regulating a proper cellular response induced by a physiological mechanical stimulus (e.g. muscle contraction) or a pathological process (e.g. brain injury). The last reviews of this issue focus on the role of Current Opinion in Cell Biology 2015, 32:v–vi

intermediate filaments in disease. Intermediate filaments are critical in the response to stress and thus can be central to the body’s response to a disease. A clear example is the upregulation of the intermediate filament network in reactive glia in the central nervous system triggered by an accute insult (brain trauma) or a chronic neurodegenerative disease, as discussed by Hol and Pekny. Furthermore, mutations in intermediate filament genes are the cause of many different devastating disorders, including neurological, heart, and skin disorders, and can also determine the organism’s response to diseases. Even though many of these diseases are defined as rare diseases, since they affect less than 1 in 2000 citizens in Europe, they pose an enormous burden on the patients and their caretakers as these diseases are often chronic, progressive, degenerative and life-threatening. Hol and Pekny shortly discuss Alexander’s disease, a fatal neurodegenerative disease caused by mutations in GFAP. Capetanaki et al. explain how mutations in desmin lead to cardiac and skeletal myopathies and Toivola et al. decribe the consequences of keratin mutations. Also mutations in nuclear intermediate filaments, the lamins, lead to severe disease phentotypes. Chatzifrangeskou et al. describe how defects in lamins which contribute to the nuclear envelope, a structural barrier that enwraps the genetic material, cause a multitude of genetic diseases that include skeletal muscle degeneration. While the nuclear envelope is crucial for proper cell functioning, it remains unclear why mutations in lamins lead to disease. Unfortunately, cure for these intermediate filament based diseases are currently non-existent and highly sought after. This unique set of reviews summarizes the state-of-the art in the field of intermediate filaments (nanofilaments) and their roles in health and disease. It comes as one of the achievements of the EU-supported Cooperation in Science and Technology (COST) action NANONET – Nanomechanics of intermediate filament networks (2010–2014), which greatly facilitated basic research and translational collaborations among the participating laboratories of excellence throughout Europe and further promoted networking with international partners outside Europe. Despite this recent progress, there is still a lack in understanding how the intermediate filament cytoskeleton contributes to mechanical resistance and mechanoresponsiveness, how the intermediate filament system is involved in cell signalling and stress response, and how mutations in the intermediate filament genes can lead to disease. A challenge in the intermediate filament field is to develop targeted therapies for the different intermediate filament based diseases, which is currently lacking. Development of such therapies is greatly dependent on a full comprehension of the biological function and nanomechanics of the different highly specialized intermediate filament cytoskeletons. www.sciencedirect.com

Editorial overview: cell architecture: intermediate filaments - from molecules to patients.

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