Keratins in health and disease Diana M Toivola 1 , Peter Boor 2,3 , Catharina Alam 1 and Pavel Strnad 4 The cytoprotective keratins (K) compose the intermediate filaments of epithelial cells and their inherited and spontaneous mutations give rise to keratinopathies. For example, mutations in K1/K5/K10/K14 cause epidermal skin diseases whereas simple epithelial K8/K18/K19 variants predispose to development of several liver disorders. Due to their abundance, tissue- and context-specific expression, keratins constitute excellent diagnostic markers of both neoplastic and non-neoplastic diseases. During injury and in disease, keratin expression levels, cellular localization or posttranslational modifications are altered. Accumulating evidence suggests that these changes modulate multiple processes including cell migration, tumor growth/metastasis and development of infections. Therefore, our understanding of keratins is shifting from diagnostic markers to active disease modifiers. Addresses 1 Department of Biosciences, Cell Biology, A ˚ bo Akademi University and Turku Center for Disease Modeling, University of Turku, Turku, Finland 2 Institute of Pathology and Department of Nephrology, RWTH University, Aachen, Germany 3 Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia 4 IZKF and Department of Internal Medicine III, University Hospital Aachen, Germany Corresponding authors: Toivola, Diana M (dtoivola@abo.fi) and Strnad, Pavel (pstrnad@ukaachen.de) Current Opinion in Cell Biology 2015, 32:73–81 This review comes from a themed issue on Cell architecture Edited by Sandrine Etienne-Manneville and Elly M Hol http://dx.doi.org/10.1016/j.ceb.2014.12.008 0955-0674/# 2014 Elsevier Ltd. All rights reserved. Introduction Keratins (K) constitute the largest subgroup of interme- diate filaments (IFs) and are expressed primarily in epi- thelial tissues, hair and skin appendages [1,2  ,3]. They consist of 54 unique genes in humans and are subclassi- fied into type I (K9–K40) and type II (K1–K8, K71–K86) family members. Keratins form obligate heteropolymers in a context- and differentiation-dependent manner. They share the characteristic tripartite structure of IFs that is made of a central, conserved a-helical rod domain and more variable N/C-terminal head/tail domains (Box 1) [1,2  ]. Keratin filament dynamics/solubility and association with binding proteins are regulated by multi- ple posttranslational modifications [4  ]. Here we focus on the non-hair keratins, that is, K1–K24 and their disease involvement discovered during the past three years. For an overview of appendage-associated keratins, please refer to an excellent review from Schweizer et al. [5], and see Figure 1 for an overview of the major hair-related diseases. Keratinopathies–inherited keratin alterations predispose to, or cause, epithelial diseases Keratins display a remarkable disease association and to date, more than 60 different disorders (termed as kera- tinopathies) have been linked to inherited keratin changes (www.interfil.org). Mutations in epidermal ker- atins (such as K1/K5/K10/K14) often occur in the most conserved keratin regions (i.e. the beginning/end of rod domain; Box 1) and cause a variety of rare skin disorders, while defects in K3/K12 and K4/K13 cause corneal and oral keratinopathies, respectively (Figure 1). In contrast, changes in K8/K18 are found in less conserved areas (Box 1) and constitute risk factors for the development, and adverse outcome of prevalent liver diseases (Figure 1). An association of K19 and K8/K18 variants with inflam- matory bowel disease has also been described but remains to be convincingly proven [3,6–9]. A large ge- nome-wide association study also implicated a frequent K5 variant as a risk factor for development of basal cell carcinoma [10]. To add to the complexity and importance of genetic modifiers in keratinopathies, mutations in the same keratin gene, or even in the same residue, can lead to different pathologies, for example, mutations in K5 give rise to epidermolysis bullosa simplex, Dowling Degos or Galli-Galli disease and mutations in K1 under- lie various hyperkeratosis disorders (www.interfil.org) [7,11] (Figure 1). This suggests that individual predis- positions co-determine which facet of the mutation will become manifest. Inherited changes: how do mutations in keratins contribute to disease development? Keratins constitute multifunctional proteins that provide mechanical stability and modulate diverse processes such as cellular polarity, migration, protein synthesis, or sus- ceptibility to apoptosis [1,2,78]. Despite this growing knowledge, the exact molecular consequences of specific human keratin variants remain only partially understood. Available online at www.sciencedirect.com ScienceDirect www.sciencedirect.com Current Opinion in Cell Biology 2015, 32:73–81