Keratin 5 and Keratin 14 (KRT5/KRT14)

Keratin 5 (KRT5) and Keratin 14 (KRT14) are type II and type I intermediate filament proteins, respectively, that heterodimerize to form the primary cytoskeletal framework of basal keratinocytes (UniProt P13647, P02533). These proteins are essential for maintaining the mechanical integrity of the epidermis, protecting cells from physical stress. In Epidermolysis Bullosa Simplex (EBS), dominant-negative mutations in either KRT5 or KRT14 disrupt filament assembly, leading to the formation of toxic mutant keratin aggregates (PubMed: 20633244). These aggregates cause the keratinocytes to become fragile and rupture upon minor mechanical trauma, resulting in painful skin blistering. Therapeutic approaches target these aggregates by using chemical chaperones like 4-phenylbutyrate to assist in protein folding or by inducing the expression of compensatory keratins such as K16 or K17 (PubMed: 21832113). Additionally, targeting the secondary inflammatory response, particularly the IL-1beta pathway triggered by these aggregates, has shown clinical promise with drugs like diacerein (PubMed: 28474301). Experimental approaches also include allele-specific siRNA to silence the mutant gene and prevent aggregate formation.

Other names

Mutant keratin aggregatesCytokeratin 5Cytokeratin 14K5K14EBS-associated mutant keratinsType II keratin 5Type I keratin 14

Inhibition of IL-1 beta signaling, induction of compensatory keratins (K16/K17), and chemical chaperone-mediated stabilization of protein folding.