Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3sigma and YAP1

The type I intermediate filament (IF) keratin 14 (K14) provides vital structural support in basal keratinocytes of epidermis. Recent studies evidenced a role for K14-dependent disulfide bonding in the organization and dynamics of keratin IFs in skin keratinocytes. Here we report that knock-in mice harboring a cysteine-to-alanine substitution at codon 373 (C373A) in Krt14 exhibit alterations in disulfide-bonded K14 species and a barrier defect secondary to enhanced proliferation, faster transit time and altered differentiation in the epidermis. A proteomics screen identified 14-3-3 as major K14 interacting proteins. Follow-up studies showed that YAP1, a transcriptional effector of Hippo signaling regulated by 14-3-3sigma in skin keratinocytes, shows aberrant subcellular partitioning and function in differentiating Krt14C373A keratinocytes. Residue C373 in K14, which is conserved in several other type I IFs, is thus revealed as a novel regulator of keratin organization and YAP function in early differentiating keratinocytes, with an impact on cell mechanics, homeostasis and barrier function in the epidermis.