776 A keratin switch promotes epidermal remodeling by organizing actomyosin-activating signals

Epidermal stability depends on keratin intermediate filaments, which form a trans-cellular mechanical scaffold. During epidermal remodeling, keratin filament composition shifts, with increased expression of five wound-associated keratin isoforms. However, the function of wound-associated keratins during epidermal remodeling remains unclear. Identifying isoform-specific keratin functions has been challenging, since depleting individual keratins compromises the more general mechanical scaffold function. To disentangle these effects, we take a gain-of-function rather than a loss-of-function approach. We find that increasing expression of wound-associated keratin 6A (K6A), but not steady-state K5, promotes keratinocyte migration, especially in stratified epidermal cultures. Using live imaging and traction force microscopy, we show that, rather than alter the keratin mechanical scaffold, K6A triggers signaling crosstalk with actomyosin to increase force generation. Unexpectedly, K6A promotes actomyosin contractility through a preferential interaction between the unstructured K6A head domain and a small pool of non-filamentous vimentin. K6A-enriched filaments and vimentin anchor a transient signaling complex spatially organizing myosin subunits and regulatory kinases to activate myosin. These results expand the functional repertoire of keratin filaments beyond their canonical role as mechanical scaffolds to include a role as signaling scaffolds, with activity tuned by the specific keratin isoforms expressed.