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 14-3-3{sigma} 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. GRAPHICAL SUMMARY O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/676359v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@23a2ccorg.highwire.dtl.DTLVardef@1952935org.highwire.dtl.DTLVardef@1c467ccorg.highwire.dtl.DTLVardef@17aa6e3_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIExpression of Keratin 9 (Krt9/K9), a keratin specific to the thicker epidermis of palmoplantar skin, increases dramatically early after birth C_LIO_LIOnset of Krt9/K9 expression follows, and is dependent on, K16, a stress-responsive keratin C_LIO_LIKrt9 null mice have aberrant nuclear YAP1 localization in differentiating keratinocytes of footpad skin C_LIO_LIPharmacological or genetic inhibition of YAP1 rescues hyperkeratosis in Krt9 null mice C_LIO_LIKeratins play a crucial role in regulating differentiation and homeostasis in skin epithelia C_LI