Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3σ and YAP1
Yajuan Guo,
Catherine J Redmond,
Krystynne A Leacock,
Margarita V Brovkina,
Suyun Ji,
Vinod Jaskula-Ranga,
Pierre A Coulombe
Affiliations
Yajuan Guo
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States; Department of Dermatology, University of Michigan Medical School, Ann Arbor, United States; Rogel Cancer Center, Michigan Medicine, University of Michigan, Ann Arbor, United States
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 Krt14’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 Krt14 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.
