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

Palmoplantar skin is structurally and molecularly distinct from Other body sites. Notably, the type 1 keratin 9 ( KRT9 /K9) is exclusively expressed in palmoplantar epidermis. Mutations in KRT9 /K9 are causative for epidermolytic palmoplantar keratoderma (EPPK), a genetic disorder typified by palmoplantar keratoderma. Surprisingly little is known about the ontogeny, regulation and significance of Krt9 /K9. Here we characterize the regulation of Krt9 /K9 in postnatal palmoplantar epidermis and uncover a novel role of K9 in modulating YAP1 signaling. Expression of Krt9/ K9 rises dramatically post-birth, following a transient induction of the stress-related keratin 16 (Krt16/ K16 ). Krt9 null mice exhibit elevated K16 and aberrant nuclear-localized YAP1 by postnatal day 3. K9 interacts with 14-3-3σ to sequesters YAP1 in the cytoplasm, while EPPK-causing pathogenic variants impair these properties. Inhibition of YAP1 in vivo ameliorates palmoplantar keratoderma in Krt9 null mice. These findings provide novel insight into the adaptation of palmoplantar skin and suggest new therapeutic avenues for diseases featuring PPKs.

Highlights: Expression of Keratin 9 ( Krt9 /K9), a keratin specific to the thicker epidermis of palmoplantar skin, increases dramatically early after birth Onset of Krt9 /K9 expression follows, and is dependent on, K16, a stress-responsive keratin Krt9 null mice have aberrant nuclear YAP1 localization in differentiating keratinocytes of footpad skin Pharmacological or genetic inhibition of YAP1 rescues hyperkeratosis in Krt9 null mice Keratins play a crucial role in regulating differentiation and homeostasis in skin epithelia.