Keratins and disease at a glance.

Keratins are cytoskeletal filament-forming proteins found in skin and other epithelial (sheet) tissues (Table 1). Keratins (type I and II), and other highly related (types III–VI) intermediate filament or nanofilament proteins, used to be thought of as very inert because they form filament networks that are not easily disrupted, in contrast to actin and microtubule cytoskeleton systems, which can be rapidly and completely dismantled by many drugs. The identification of causative pathogenic mutations in the keratin genes KRT5 and KRT14 in the human blistering skin disease epidermolysis bullosa simplex (EBS) changed this view and demonstrated the importance of these proteins for maintaining tissue resilience (Bonifas et al., 1991; Coulombe et al., 1991; Lane et al., 1992). As the firstreported disease caused by keratin mutations, EBS set the pattern for all the other keratin disorders, as well as several non-keratin genetic skin diseases. Many ‘keratinopathies’ have now been identified with a variety of disease phenotypes, often predicted by tissue-specific keratin expression, with pathology usually involving some form of tissue fragility (Szeverenyi et al., 2008; see poster). By reviewing the essential elements of keratin protein structure and filament assembly, we consider how keratin filaments provide tissues with mechanical resilience, and how mutations might impact upon these processes and compromise tissue function. The rare human keratinopathies have provided important clues to keratin function, revealing the potential roles for keratins in many types of stress response, and even effects on membrane trafficking and cell and tissue differentiation. This knowledge has begun to inform development of therapeutic options for keratin diseases, and successful first-in-man siRNA trials have been performed. We conclude by considering the issues and challenges now facing the field, and how they are or can be addressed.