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

Abstract

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 colleagu...

Atomic structure of the vimentin central α-helical domain and its implications for intermediate filament assembly

“…Recently, an increasing number of reports suggested links between point mutations in various IF proteins and over 80 currently incurable human diseases, including muscle, heart, skin, and neurological disorders (16). To get a mechanistic insight into both normal and pathogenic IF behaviour, a detailed three-dimensional structure is indispensable.…”

Investigating Cellular Nanoscale with X-rays

“…Intermediate filaments are of high interest, due to their role and function in cells, but also because about 70 different types of IFs exist in humans [107]. While microfilaments and microtubules remain the same over all the cell types, the IFs are classified into six sequence homology classes (SHCs).…”

“…vimentin is found in fibroblasts, neurofilaments in neurons, or keratin in epithelial cells (section 1.4). The biomedical importance of studying IF proteins is high as many diseases involve IFs mutations [107,112,[179][180][181]. For example, the clumping of keratin IFs is involved in epidermolytic hyperkeratosis.…”

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

“…In the liver, keratin mutations do not cause disease per se but clearly contribute or predispose to disease when liver cells are exposed to additional stress, emphasizing the role of keratins during cell stress or cell injury 10, 14. In mouse models, knock‐down or expression of mutant simple epithelial K8 or K18, phenocopy human conditions and cause or predispose to a range of pathologies and abnormalities in the organs where these keratins are expressed, such as in the intestine, liver and thymus 10, 15, 16. K8 knockout (K8 −/− ) in mice, for example, causes 50% embryonic lethality and leads to an ulcerative‐colitis‐like phenotype in the surviving mice 17, 18.…”