Intermediate Filaments Structure, Function and Clinical Significance

Intermediate filaments (IFs) are versatile cytoskeletal structures formed by members of a wide family of proteins. IFs are involved in essential cellular processes, such as cell dynamics and integrity, division and migration, as well as in pathophysiology. Structurally, most IFs have a diameter of approximately 10-12 nm, in between those of actin microfilaments (6 nm) and microtubules (25 nm), which is the origin of the term “intermediate”. On the basis of amino acid sequence homology, IF proteins have been divided into five main types, including keratins (acidic) (type I), keratins (basic) (type II), vimentin, GFAP and desmin (type III), nestin and neurofilaments (type IV), and nuclear lamins (type V). IF proteins share a common secondary structure, consisting of a central α-helical rod domain flanked by non-α-helical N-terminal ‘head’ domain and C-terminal ‘tail’ domain. Two individual polypeptide chains associate into parallel dimers, which subsequently form anti-parallel, half-staggered tetramers that associate laterally to form unit-length filaments (ULFs). These ULFs then connect end to end to form filaments. Unlike actin microfilaments and microtubules, IFs show no polarity. Moreover, they can undergo reorganization at any point of their length.

IFs not only regulate cellular mechanics but are also integrate various intra- and intercellular structures and processes, making them arguably a critical "crisis command center" among cell and tissue networks. Importantly, IFs can be modulated and, in turn, modulate signaling events through their post-translational modification (PTM). Accordingly, IFs are essential in a variety of biological processes in health and disease: IFs are essential to protect the nucleus form mechanical stress, and are key for organelle position and function; lamin A/C downregulation in neutrophils allows them to distort their nuclei and pass-through narrow spaces during trans-endothelial migration; the hallmark of the epithelial-mesenchymal transition (EMT) is vimentin upregulation and keratin downregulation; vimentin is very important in host-pathogen interactions; keratin mutations have been clarified in a range of genetic skin disorders, whereas mutations in the corresponding IFs underlie laminopathies and desminopathies. Recently, diagnostic and therapeutic strategies targeting IFs are envisaged for many human diseases, including pathogen infections, inflammatory diseases, degenerative muscle and brain diseases, skin diseases, and various cancers.

This research topic aims to bring together researchers from cell biology, biophysics, mechanobiology, microbiology, immunology, biomedical engineering, and translational and clinical sciences to highlight recent advances and new approaches relevant to the IFs field. The major goal of this research topic is to initiate new ideas and collaborations to deepen our understanding of IFs and their biological roles in cells and their associated human diseases.

This Research Topic aims to highlight recent advances that address the IFs structure, function and clinical significance. We welcome Original Research Articles and Reports, Reviews, Methods, Perspective and Opinion articles. Subtopics include, but are not limited to:
• Role of IFs in cell mechanics, migration, growth, differentiation;
• Pathogenic function of IFs in wound healing, physical and biochemical stimuli, oxidative stress and pathogen infection;
• Cellular signaling controls of IFs;
• Interactions between IFs and other cytoskeletal network and organelles;
• In vitro reconstitution studies of IFs structure and dynamics;
• Advances in imaging or optogenetics tools to document or manipulate IFs dynamics and mechanics;
• Regulation of IFs dynamics and mechanics by associated proteins;
• Development of new methods or tools to study IFs in vitro and in vivo;
• Clinical applications of IFs.