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

• Published in: eLife Vol. 9
• Main Authors: Guo, Yajuan, Redmond, Catherine J, Leacock, Krystynne A, Brovkina, Margarita V, Ji, Suyun, Jaskula-Ranga, Vinod, Coulombe, Pierre A
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 05.05.2020; eLife Sciences Publications, Ltd
• Subjects: 14-3-3; 14-3-3 protein; 14-3-3 Proteins - metabolism; 14-3-3 Proteins - physiology; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Alanine; Animals; Cell Biology; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; CRISPR; Epidermis; Epidermis - metabolism; Epidermis - physiology; Epidermis - ultrastructure; Female; Gene Knock-In Techniques; hippo; Histology; Homeostasis; intermediate filament; Keratin; Keratin-14 - metabolism; Keratin-14 - physiology; keratinocyte; Keratinocytes; Keratinocytes - metabolism; Keratinocytes - physiology; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Physiology; Proteins; Proteomics; Skin; Transcription; Yes-associated protein; Young adults; 14-3-3; mouse; cell biology; intermediate filament; hippo; keratinocyte; skin; epidermis
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.53165

The intermediate filament protein 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 's codon 373 (C373A) exhibit alterations in disulfide-bonded K14 species and a barrier defect secondary to enhanced proliferation, faster transit time and altered differentiation in epidermis. A proteomics screen identified 14-3-3 as 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 C373A keratinocytes. Residue C373 in K14, which is conserved in a subset of keratins, is 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 epidermis.