“IF-pathies”: a broad spectrum of intermediate filament–associated diseases

Intermediate filaments (IFs) are encoded by the largest gene family among the three major cytoskeletal protein groups.Unique IF compliments are expressed in selective cell types, and this expression is reflected in their involvement, upon mutation, as a cause of or predisposition to more than 80 human tissue-specific diseases.This Review Series covers diseases and functional and structural aspects pertaining to IFs and highlights the molecular and functional consequences of IF-associated diseases (IF-pathies).Exciting challenges and opportunities face the IF field, including developing both a better understanding of the pathogenesis of IF-pathies and targeted therapeutic approaches. Intermediate filamentsIntermediate filaments (IFs), microfilaments (MFs), and microtubules (MTs) are the major fibrillar cytoplasmic elements that make up what is referred to as the cytoskeleton.IFs consist of a large protein family that includes 73 unique gene products, which places the genes encoding them among the 100 largest gene families in humans (1).The IF proteins are grouped into six types (types I-VI): those in types I-IV are found in the cytoplasm, the type V IF proteins are found in the nucleus, and those classified as type VI are found exclusively in the lens (Table 1).Several features distinguish IFs (2-4) from MFs and MTs, including IF structural diversity, tissue-and cell-selective expression, unique subcellular compartment distribution (lamins are found in the nucleus, whereas the remaining IFs are in the cytoplasm), relative insolubility, nucleotide-independent assembly, restricted expression to higher eukaryotes, and, most relevant, their involvement in more than 80 human diseases (Human Intermediate Filament Database, http://www.interfil.org/index.php)(5).Another distinguishing feature of IFs is their regulation (primarily but not exclusively) by phosphorylation, whereas MFs and MTs are regulated preferentially but not exclusively by their associated proteins and posttranslational modifications other than phosphorylation (6).Furthermore, IFs are characteristically resistant to breakage when mechanically stressed, whereas MFs and MTs are far less compliant (7).In addition to the unique and complex cell and tissue distribution of IFs (Figure 1), the expression of some IF proteins is highly regulated during development and cell differentiation and can be markedly induced in cells and tissues undergoing an injury response.For example, keratin 5 and 14 (K5/K14) are found in basal keratinocytes, whereas K1/K10 are found in the differentiating layers of suprabasal epidermis (8); K19 is found in fetal but not normal adult hepatocytes (9); K19/K20 (10) and K6/K16 (11) are highly induced in response to pancreatic acinar cell and skin injury, respectively; and glial fibrillary acidic protein (GFAP) is upregulated during reactive gliosis (12). The Review SeriesThe Review Series herein includes eight state-of-the-art treatises by leaders in the field.The first article, by John Eriksson, Robert Goldman, and colleagues, sets the stage by providing a historical perspective of IFs and their classification (13).It also provides several functional perspectives with an emphasis on the paradigm shifting notion that IFs are not only structural proteins but also play essential roles as signaling organizers and buffers of cellular stress (13).The second Review, by Harald Herrmann, Sergei Strelkov, Peter Burkhard, and Ueli Aebi, highlights some of the structural features of IFs versus MFs and MTs and describes the current understanding of the assembly properties of IFs and how IF mutations affect IF structure and assembly properties (14).The remaining six articles cover specific members of the IF protein family in the sequential order of IF types I-VI.The type I and type II keratins are covered in the third and fourth reviews (15, 16).Pierre Coulombe, Michelle Kerns, and Elaine Fuchs discuss K5 and K14 and how mutations in the genes encoding these proteins are responsible for epidermolysis bullosa simplex (EBS), the first human disease known to be linked to an IF gene (15).Nam-On Ku, Pavel Strnad, Shinichiro Hanada, and Bishr Omary discuss the simple epithelial keratins and how mutations in the genes encoding K8, K18, and K19 serve as liver-disease modifiers (16).These authors also summarize the role of K8 and K18 in the hepatocyte inclusions, termed Mallory-Denk bodies, that are seen in several human liver diseases (16).In the fifth review, Lev Goldfarb and Marinos Dalakas discuss the type III IF protein desmin and its role in skeletal and cardiac myopathies (17).Ronald Liem and Albee Messing discuss, in the sixth review, the IF proteins found in glial cells and neurons, which include both type III and type IV IF proteins, and their involvement in several neurodegenerative disorders and inclusion formation (18).In the seventh review, Harold Worman, Stephen Young, and colleagues tackle laminopathies, the diseases caused by mutations in the genes encoding the type V IF proteins, the lamins, and discuss how cell biology and physiology efforts are providing unique therapeutic approaches to the highly complex disorders caused by lamin A/C gene mutations (19).Finally, Roy Quinlan and colleagues discuss the type VI beaded filament proteins of the eye lens and how their mutation leads to cataract formation in animal models and humans (20). Conflict of interest:The author has declared that no conflict of interest exists.