Under Pressure: A unique mechanoresponsive mechanism of body site-specific keratin regulation in palmoplantar epidermis

The palmoplantar epidermis, in adapting to the exceptional mechanical strain it bears during locomotion, is molecularly and histologically distinct from other body sites. However, the mechanisms specifying and maintaining its distinct identity remain incompletely defined. Here, we identify the type 1 keratin 9 (KRT9/K9), a protein uniquely expressed in the palmoplantar epidermis, as a key modulator of mechanosensitive YAP1 signaling in response to postnatal mechanical compression. K9 loss-of-function variants, as observed in human KRT9 palmoplantar epidermal differentiation disorder (KRT9-pEDD), results in aberrant YAP1 subcellular partitioning and elevated levels of the stress-induced keratin 16 (KRT16/K16). Krt9 null mice recapitulate these molecular phenotypes as early as postnatal day 3 (P3). We further identify dynamic, YAP1-dependent regulation of Krt9/K9 and Krt16/K16 during early postnatal development and in response to ex vivo mechanical compression, highlighting the role of mechanical stress in epidermal specification. Mechanistically, K9 interacts with the YAP1 binding protein 14-3-3σ and sequesters YAP1 in the cytoplasm, inhibiting its transcriptional activity; these functions are disrupted by KRT9-pEDD-causing variants in K9. Notably, genetic or pharmacological inhibition of YAP1 ameliorates palmoplantar keratoderma in Krt9 null mice. These findings provide insight into the influence of mechanical force in specification and maintenance of palmoplantar skin and suggest new therapeutic interventions for inherited palmoplantar epidermal differentiation disorders (pEDDs).