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

SummaryThe 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.

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692 Keratin-14 dependent disulfide bonding contributes to epidermal homeostasis and barrier function through 14-3-3 and Hippo signaling in mouse skin in vivo

Journal of Investigative Dermatology ◽

10.1016/j.jid.2018.03.701 ◽

2018 ◽

Vol 138 (5) ◽

pp. S118

Author(s):

Y. Guo ◽

K. Leacock ◽

V. Ranganathan ◽

P. Coulombe

Keyword(s):

Barrier Function ◽

Mouse Skin ◽

Hippo Signaling ◽

Disulfide Bonding ◽

Keratin 14 ◽

Epidermal Homeostasis

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

10.7554/elife.53165.sa1 ◽

2019 ◽

Keyword(s):

Barrier Function ◽

Keratin 14 ◽

Epidermal Homeostasis

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

eLife ◽

10.7554/elife.53165 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Yajuan Guo ◽

Catherine J Redmond ◽

Krystynne A Leacock ◽

Margarita V Brovkina ◽

Suyun Ji ◽

...

Keyword(s):

Barrier Function ◽

Intermediate Filament Protein ◽

Hippo Signaling ◽

Structural Support ◽

Skin Keratinocytes ◽

Keratin 14 ◽

Barrier Defect ◽

Epidermal Homeostasis ◽

And Function ◽

Filament Protein

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.

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Essential Role of Polarity Protein Par3 for Epidermal Homeostasis through Regulation of Barrier Function, Keratinocyte Differentiation, and Stem Cell Maintenance

Journal of Investigative Dermatology ◽

10.1016/j.jid.2016.07.011 ◽

2016 ◽

Vol 136 (12) ◽

pp. 2406-2416 ◽

Cited By ~ 13

Author(s):

Noelle J.A. Ali ◽

Martim Dias Gomes ◽

Ronja Bauer ◽

Susanne Brodesser ◽

Catherin Niemann ◽

...

Keyword(s):

Stem Cell ◽

Barrier Function ◽

Essential Role ◽

Keratinocyte Differentiation ◽

Stem Cell Maintenance ◽

Epidermal Homeostasis ◽

Cell Maintenance

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Animal Models for Retinoid Receptor Research: Implications for Epidermal Homeostasis, Skin Barrier Function, Wound Healing, and Atopic Dermatitis

Basic and Clinical Dermatology - Retinoids and Carotenoids in Dermatology ◽

10.3109/9781420021189.002 ◽

2007 ◽

pp. 27-54 ◽

Cited By ~ 1

Author(s):

Norbert B. Ghyselinck ◽

Pierre Chambon

Keyword(s):

Wound Healing ◽

Atopic Dermatitis ◽

Animal Models ◽

Barrier Function ◽

Skin Barrier ◽

Skin Barrier Function ◽

Retinoid Receptor ◽

Epidermal Homeostasis ◽

Receptor Research

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Faculty Opinions recommendation of Essential Role of Polarity Protein Par3 for Epidermal Homeostasis through Regulation of Barrier Function, Keratinocyte Differentiation, and Stem Cell Maintenance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726579946.793533437 ◽

2017 ◽

Author(s):

Ian Macara

Keyword(s):

Stem Cell ◽

Barrier Function ◽

Essential Role ◽

Keratinocyte Differentiation ◽

Stem Cell Maintenance ◽

Epidermal Homeostasis ◽

Cell Maintenance

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A Novel Multi-Action Emollient Plus Cream Improves Skin Barrier Function in Patients with Atopic Dermatitis: In vitro and Clinical Evidence

Skin Pharmacology and Physiology ◽

10.1159/000513055 ◽

2021 ◽

Vol 34 (1) ◽

pp. 8-18

Author(s):

Marika Quadri ◽

Roberta Lotti ◽

Laura Bonzano ◽

Silvana Ciardo ◽

Mario Bruno Guanti ◽

...

Keyword(s):

Atopic Dermatitis ◽

Barrier Function ◽

Randomized Study ◽

Skin Barrier ◽

Lower Limbs ◽

Skin Barrier Function ◽

Tape Stripping ◽

Epidermal Thickness ◽

Epidermal Homeostasis

Background: Emollients capable of restoring the skin barrier function would extend their role beyond basic maintenance therapy in atopic dermatitis (AD). Objectives: Investigate the effect of a novel emollient plus cream (EC; Dermoflan®) on the skin barrier in vitro and in patients with mild-to-moderate AD. Methods: The effect of EC on the skin barrier recovery was evaluated using a tape-stripping (TS) model. After TS, organ cultures were treated with EC (undiluted or diluted 1:1 with water) and analyzed at 18–120 h using hematoxylin and eosin, Oil Red O, immunohistochemical, and immunofluorescent techniques. In a double-blind, randomized study, EC or placebo was applied once daily for 2 months to antecubital folds of the upper and lower limbs of patients with mild-to-moderate AD in clinical remission. Epidermal thickness, vascularization, and epidermal hydration were assessed by optical coherence tomography and corneometry, respectively, at baseline, and 1 and 2 months following treatment initiation. Results: Following TS, EC treatment significantly increased epidermal thickness and lipid content versus diluent in the skin organ culture, as well as claudin-1, involucrin, and caspase-14 expression, suggesting skin barrier repair. EC treatment also decreased keratin-16 expression and increased levels of Toll-like receptors 1 and 2 versus diluent, suggesting involvement in regulating the epidermal immune response. In 20 patients randomized 1:1 to EC or placebo, EC treatment at the elbow fold/popliteal fossa significantly decreased epidermal thickness after 2 months, and the number of blood vessels at the elbow fold after 1 and 2 months, versus placebo. EC significantly improved the skin hydration after 2 months versus baseline. Conclusions: This novel multi-action EC may help to restore epidermal homeostasis and improve the skin of patients with AD. Results indicate that this novel multi-action EC could be a valid adjuvant therapy in patients with AD. Key Message: Novel multi-action emollient cream helps to restore epidermal homeostasis and improves the skin affected by AD.

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