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

  1. Yajuan Guo
  2. Catherine J Redmond
  3. Krystynne A Leacock
  4. Margarita V Brovkina
  5. Suyun Ji
  6. Vinod Jaskula-Ranga
  7. Pierre A Coulombe  Is a corresponding author
  1. University of Michigan Medical School, United States
  2. Johns Hopkins University School of Medicine, United States

Abstract

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.

Data availability

ALL of the data generated or analyzed during this study are included in the manuscript and supporting files. The entire data set making up the submission to eLife has been deposited in BioXriv (BIORXIV/2019/824219).

Article and author information

Author details

  1. Yajuan Guo

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Catherine J Redmond

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Krystynne A Leacock

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Margarita V Brovkina

    Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Suyun Ji

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vinod Jaskula-Ranga

    Department of Ophtalmology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Pierre A Coulombe

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    For correspondence
    coulombe@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0680-2373

Funding

National Institutes of Health (AR042047)

  • Pierre A Coulombe

National Institutes of Health (5T32CA009676)

  • Catherine J Redmond

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of Michigan. Every effort was made to minimize suffering.

Reviewing Editor

  1. Valerie Horsley, Yale University, United States

Publication history

  1. Received: October 30, 2019
  2. Accepted: May 4, 2020
  3. Accepted Manuscript published: May 5, 2020 (version 1)
  4. Version of Record published: May 26, 2020 (version 2)

Copyright

© 2020, Guo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yajuan Guo
  2. Catherine J Redmond
  3. Krystynne A Leacock
  4. Margarita V Brovkina
  5. Suyun Ji
  6. Vinod Jaskula-Ranga
  7. Pierre A Coulombe
(2020)
Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3σ and YAP1
eLife 9:e53165.
https://doi.org/10.7554/eLife.53165
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