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

Guo, Yajuan; Leacock, Krystynne A; Redmond, Catherine J.; Jaskula-Ranga, Vinod

doi:10.1101/824219

Cited by 6 publications

(12 citation statements)

References 78 publications

(100 reference statements)

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“…The link between YAP1 and the intervertebral disc in the Hippo pathway has been concentrated on NP cells or rat models in recent years, The expression of YAP1 affected the transcription level of COL2A1 and ACAN in human chondrocytes might lead to degeneration of human cartilage chondrocytes. YAP1 also regulates the proliferation of human cartilage chondrocytes, which is similar to previous reports that YAP1 could improve cellular proliferation, such as keratinocytes (Guo et al, 2020) and limbal stem cell (Hou et al, 2020). Therefore, we propose that YAP1 might play an important role in regulating mechanical tension-mediated human endplate cartilage degeneration.…”

Section: Discussionsupporting

confidence: 89%

YAP1 controls degeneration of human cartilage chondrocytes in response to mechanical tension

Ding

Xiao

2022

Cell Biology International

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Disc herniation is a kind of disease caused by degenerative discs, which is common in the elderly, bringing substantial financial burden to families and society. Mechanical tension has a vital effect on the maintenance of cartilage function, however, the molecular mechanism by which mechanical tension causes degenerative discs to remain unclear. This study was the first to reveal Yes‐associated protein 1(YAP1) is a key regulator in mechanical tension‐mediated degenerative discs. Activation of YAP1 may be a valuable strategy to delays the degeneration of human cartilage chondrocytes. We found that YAP1 expression was significantly decreased in degenerative human endplate cartilage and tissue with the strength and time of mechanical stimulation, but the cell cycle distribution was significantly changed under the 10% cyclic mechanical tension(CMT). Besides, the degeneration of endplate cartilage can be delayed by activating the expression level of YAP1 in vitro and it has also been verified in the cartilage endplate tissue in vitro. Furthermore, We found that YAP1 and TEAD1 overexpression increased the activity of the ACAN or COL2A1 promoter to enhance the transcriptional activity of human chondrocyte collagen. The CMT activates the classic Hippo signaling pathway of YAP1, and piezo1 may regulate YAP1 expression through the Hippo signaling pathway. In conclusion, these results suggest the novel mechanism of YAP contributes to delaying the degeneration of endplate cartilage and targeting YAP in combination with Piezo1 is a potential therapeutic approach for the treatment of endplate cartilage degeneration.

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Section: Discussionsupporting

confidence: 89%

YAP1 controls degeneration of human cartilage chondrocytes in response to mechanical tension

Ding

Xiao

2022

Cell Biology International

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“…Further correlating these studies, as well as measurements of K10 protein on a single-cell level would likely prove highly informative in understanding the nature of keratinocyte commitment to differentiation. This is especially important considering evidence for a role of post-translational modifications in keratinocyte differentiation (Guo et al 2020) and will further establish our defintions of low/high expression of genes/protein and their transitions across keratinocytes differentiation and cycling.…”

Section: Main Textmentioning

confidence: 95%

“…Finally, one wonders about the significance and role, if any, of the mixing of progenitor-type (e.g., K5, K14, K15) and differentiation-type (e.g., K1, K10) keratins in hybrid keratinocytes at the time of their commitment to differentiation. A recent study provided strong evidence that K14-dependent disulfide bonding regulates a YAP1/Hippo-driven mechanism that gates entry of keratinocytes into differentiation within epidermis, with the key biochemical determinants conserved in some type I keratins (e.g, K10, K9) but not others (e.g., K15, K19) (Guo et al, 2020). Recent advances in spatial mRNA-seq (Marx 2021) further provide opportunities to observe transcriptional changes of keratinocytes as they initiate and undergo differentiation.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Revisiting the significance of keratin expression in complex epithelia

Cohen

Johnson

Redmond

et al. 2022

Preprint

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A large group of keratin genes (n=54 in the human genome) code for intermediate filament (IF)-forming proteins and show differential regulation in epithelial cells and tissues. Keratin expression can be highly informative about the type of epithelial tissue, differentiation status of constituent cells, and biological context (e.g., normal vs. diseased settings). The foundational principles underlying the use of keratin expression to gain insight about epithelial cells and tissues primarily originated in pioneering studies conducted in the 1980s. The recent emergence of single cell transcriptomics provides an opportunity to revisit these principles and gain new insight into epithelial biology. Re-analysis of single cell RNAseq data collected from human and mouse skin has confirmed long-held views regarding the quantitative importance and pairwise regulation of specific keratin genes in keratinocytes of surface epithelia. Further, such analyses confirm and extend the notion that changes in keratin gene expression occur gradually as progenitor keratinocytes commit to and undergo differentiation, and challenge the prevailing assumption that specific keratin combinations reflect a mitotic vs. a post-mitotic, differentiating state. Our findings provide a blueprint for similar analyses in other tissues, and warrant a more nuanced approach in the use of keratin genes as biomarkers in epithelia.

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“…Overall, Krt14 and Krt15 are similar in their amino acid composition (~81% amino acid homology), however, there are important biochemical differences between them. For example, Krt14 has a Cysteine residue in position 373 (Alanine in Krt15) which has been shown to form interfilamentous di-sulfate bonds (15)(16)(17). These cross-linkages have been shown to alter nuclear shape and act as recruitment sites for signal cascades in differentiating keratinocytes (15).…”

Section: Introductionmentioning

confidence: 99%

Krt14 and Krt15 differentially regulate regenerative properties and differentiation potential of airway basal cells

Ievlev¹,

Lynch²,

Freischlag³

et al. 2023

JCI Insight

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Keratin expression dynamically changes in airway basal cells (BCs) following acute and chronic injury, yet the functional consequences of these changes on BC behavior remain unknown. In Bronchiolitis Obliterans (BO) following lung transplantation, BC clonogenicity declines which is associated with a switch from keratin15 (Krt15) to keratin14 (Krt14). We investigated the roles of these keratins using Crispr-KO in vitro and in vivo and found that Krt14-KO and Krt15-KO produce contrasting phenotypes in terms of differentiation and clonogenicity. Primary mouse Krt14-KO BCs failed to differentiate into club and ciliated cells, but had enhanced clonogenicity.By contrast, Krt15-KO did not alter BC differentiation, but impaired clonogenicity in vitro and reduced the number of label-retaining BCs in vivo following injury. Krt14, but not Krt15, bound the tumor suppressor stratifin (Sfn). Disruption of Krt14, but not of Krt15, reduced Sfn protein abundance and increased expression of the oncogene dNp63a during BC differentiation, while dNp63a levels were reduced in Krt15-KO BCs. Overall, the phenotype of Krt15-KO BCs contrasts that of Krt14-KO and resembles the phenotype in BO with decreased clonogenicity, increased Krt14 and decreased dNp63a expression. This work demonstrates that Krt14 and Krt15 functionally regulate BC behavior which is relevant in chronic disease states like BO.

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

Cited by 6 publications

References 78 publications

YAP1 controls degeneration of human cartilage chondrocytes in response to mechanical tension

YAP1 controls degeneration of human cartilage chondrocytes in response to mechanical tension

Revisiting the significance of keratin expression in complex epithelia

Krt14 and Krt15 differentially regulate regenerative properties and differentiation potential of airway basal cells

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