scholarly journals A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases.

1991 ◽  
Vol 115 (6) ◽  
pp. 1661-1674 ◽  
Author(s):  
P A Coulombe ◽  
M E Hutton ◽  
R Vassar ◽  
E Fuchs
Keyword(s):  
Transgenic Mice ◽  
Basal Cell ◽  
Epidermolysis Bullosa ◽  
Single Gene ◽  
Basal Layer ◽  
Structural Function ◽  
Epidermolysis Bullosa Simplex ◽  
Physical Trauma ◽  
Keratin Filament ◽  
Filament Network

Previously we demonstrated that transgenic mice expressing a mutant keratin in the basal layer of their stratified squamous epithelia exhibited a phenotype bearing resemblance to a subclass (Dowling Meara) of a heterogeneous group of human skin disorders known as epidermolysis bullosa simplex (EBS) (Vassar, R., P. A. Coulombe, L. Degenstein, K. Albers, E. Fuchs. 1991. Cell. 64:365-380.). The extent to which subtypes of EBS diseases might be genetically related is unknown, although they all exhibit skin blistering as a consequence of basal cell cytolysis. We have now examined transgenic mice expressing a range of keratin mutants which perturb keratin filament assembly to varying degrees. We have generated phenotypes which include most subtypes of EBS, demonstrating for the first time that at least in mice, these diseases can be generated by different mutations within a single gene. A strong correlation existed between the severity of the disease and the extent to which the keratin filament network was disrupted, implicating perturbations in keratin networks as an essential component of these diseases. Some keratin mutants elicited subtle perturbations, with no signs of the tonofilament clumping typical of Dowling-Meara EBS and our previous transgenic mice. Importantly, basal cell cytolysis still occurred, thereby uncoupling cytolysis from the generation of large, insoluble cytoplasmic protein aggregates. Moreover, cell rupture occurred in a narrowly defined subnuclear zone, and seemed to involve three factors: (a) filament perturbation, (b) the columnar shape of the basal cell, and (c) physical trauma. This work provides the best evidence to date for a structural function of a cytoplasmic intermediate filament network, namely to impart mechanical integrity to the cell in the context of its tissue.

scholarly journals Damaged Keratin Filament Network Caused by KRT5 Mutations in Localized Recessive Epidermolysis Bullosa Simplex

2021 ◽  
Vol 12 ◽  
Author(s):  
Fuying Chen ◽  
Lei Yao ◽  
Xue Zhang ◽  
Yan Gu ◽  
Hong Yu ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Mapk Signaling ◽  
Epidermolysis Bullosa Simplex ◽  
Protein Levels ◽  
Keratin 5 ◽  
Keratin Filament ◽  
Filament Network ◽  
Keratin Intermediate Filaments ◽  
Desmosomal Protein

Epidermolysis bullosa simplex (EBS) is a blistering dermatosis that is mostly caused by dominant mutations in KRT5 and KRT14. In this study, we investigated one patient with localized recessive EBS caused by novel homozygous c.1474T > C mutations in KRT5. Biochemical experiments showed a mutation-induced alteration in the keratin 5 structure, intraepidermal blisters, and collapsed keratin intermediate filaments, but no quantitative change at the protein levels and interaction between keratin 5 and keratin 14. Moreover, we found that MAPK signaling was inhibited, while desmosomal protein desmoglein 1 (DSG1) was upregulated upon KRT5 mutation. Inhibition of EGFR phosphorylation upregulated DSG1 levels in an in vitro model. Collectively, our findings suggest that this mutation leads to localized recessive EBS and that keratin 5 is involved in maintaining DSG1 via activating MAPK signaling.

scholarly journals Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex

2021 ◽  
Vol 22 (22) ◽  
pp. 12446
Author(s):  
Nadezhda A. Evtushenko ◽  
Arkadii K. Beilin ◽  
Anastasiya V. Kosykh ◽  
Ekaterina A. Vorotelyak ◽  
Nadya G. Gurskaya
Keyword(s):  
Er Stress ◽  
Epidermolysis Bullosa ◽  
Trigger Point ◽  
Basal Layer ◽  
Sterile Inflammation ◽  
Global Changes ◽  
Epidermolysis Bullosa Simplex ◽  
Molecular Pattern ◽  
Signaling Activation ◽  
Cellular Pathology

Epidermolysis bullosa simplex (EBS) is a group of inherited keratinopathies that, in most cases, arise due to mutations in keratins and lead to intraepidermal ruptures. The cellular pathology of most EBS subtypes is associated with the fragility of the intermediate filament network, cytolysis of the basal layer of the epidermis, or attenuation of hemidesmosomal/desmosomal components. Mutations in keratins 5/14 or in other genes that encode associated proteins induce structural disarrangements of different strengths depending on their locations in the genes. Keratin aggregates display impaired dynamics of assembly and diminished solubility and appear to be the trigger for endoplasmic reticulum (ER) stress upon being phosphorylated by MAPKs. Global changes in cellular signaling mainly occur in cases of severe dominant EBS mutations. The spectrum of changes initiated by phosphorylation includes the inhibition of proteasome degradation, TNF-α signaling activation, deregulated proliferation, abnormal cell migration, and impaired adherence of keratinocytes. ER stress also leads to the release of proinflammatory danger-associated molecular pattern (DAMP) molecules, which enhance avalanche-like inflammation. Many instances of positive feedback in the course of cellular stress and the development of sterile inflammation led to systemic chronic inflammation in EBS. This highlights the role of keratin in the maintenance of epidermal and immune homeostasis.

scholarly journals Hemidesmosomes Show Abnormal Association with the Keratin Filament Network in Junctional Forms of Epidermolysis Bullosa

1998 ◽  
Vol 110 (2) ◽  
pp. 132-137 ◽  
Author(s):  
James R. McMillan ◽  
John A. McGrath ◽  
Michael J. Tidman ◽  
Robin A.J. Eady
Keyword(s):  
Epidermolysis Bullosa ◽  
Keratin Filament ◽  
Filament Network

scholarly journals The basal keratin network of stratified squamous epithelia: defining K15 function in the absence of K14.

1995 ◽  
Vol 129 (5) ◽  
pp. 1329-1344 ◽  
Author(s):  
C Lloyd ◽  
Q C Yu ◽  
J Cheng ◽  
K Turksen ◽  
L Degenstein ◽  
...  
Keyword(s):  
Basal Layer ◽  
Mutant Mice ◽  
Epidermolysis Bullosa Simplex ◽  
Keratin 5 ◽  
Keratin Filaments ◽  
Squamous Epithelia ◽  
Key Factor ◽  
Keratin Filament ◽  
Bona Fide ◽  
Basal Keratin

Keratin 5 and keratin 14 have been touted as the hallmarks of the basal keratin networks of all stratified squamous epithelia. Absence of K14 gives rise to epidermolysis bullosa simplex, a human blistering skin disorder involving cytolysis in the basal layer of epidermis. To address the puzzling question of why this disease is primarily manifested in skin rather than other stratified squamous epithelia, we ablated the K14 gene in mice and examined various tissues expressing this gene. We show that a key factor is the presence of another keratin, K15, which was hitherto unappreciated as a basal cell component. We show that the levels of K15 relative to K14 vary dramatically among stratified squamous epithelial tissues, and with neonatal development. In the absence of K14, K15 makes a bona fide, but ultrastructurally distinct, keratin filament network with K5. In the epidermis of neonatal mutant mice, K15 levels are low and do not compensate for the loss of K14. In contrast, the esophagus is unaffected in the neonatal mutant mice, but does appear to be fragile in the adult. Parallel to this phenomenon is that esophageal K14 is expressed at extremely low levels in the neonate, but rises in postnatal development. Finally, despite previous conclusions that the formation of suprabasal keratin filaments might depend upon K5/K14, we find that a wide variety of suprabasal networks composed of different keratins can form in the absence of K14 in the basal layer.

Temperature sensitivity of the keratin cytoskeleton and delayed spreading of keratinocyte lines derived from EBS patients

1995 ◽  
Vol 108 (11) ◽  
pp. 3463-3471 ◽  
Author(s):  
S.M. Morley ◽  
S.R. Dundas ◽  
J.L. James ◽  
T. Gupta ◽  
R.A. Brown ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Cell Lines ◽  
Epidermolysis Bullosa ◽  
Intermediate Filament ◽  
Time Window ◽  
T Antigen ◽  
Epidermal Keratinocytes ◽  
Epidermolysis Bullosa Simplex ◽  
Hpv16 E6 ◽  
Filament Network

Point mutations in the keratin intermediate filament genes for keratin 5 or keratin 14 are known to cause hereditary skin blistering disorders such as epidermolysis bullosa simplex, in which epidermal keratinocytes are extremely fragile and the skin blisters on mild trauma. We show that in 2 phenotypically diverse cases of epidermolysis bullosa simplex, the keratin mutations result in a thermoinstability of the intermediate filament cytoskeleton which can be reproducibly demonstrated even in the presence of tissue culture-induced keratins and in conditions where filament fragility is not otherwise obvious. SV40-T antigen and HPV16 (E6--E7) immortalised keratinocyte cell lines were examined, established from control and epidermolysis bullosa simplex-affected individuals with either severe (Dowling-Meara) or mild (Weber-Cockayne) forms of the disease. In standard tissue culture conditions no significant and consistent abnormality of the keratin cytoskeleton could be demonstrated. However after thermal stress a reduced stability of the keratin filaments was demonstrable in the epidermolysis bullosa simplex cell lines, with filaments breaking into aggregates similar to those seen in skin from EBS patients. These aggregates were maximal at 15 minutes after heat shock and the filament network structure was substantially reversed by 60 minutes. Differences were also seen in the cells during respreading after replating: cells containing mutant keratins were slower to respread than controls and fine aggregates were seen at the cell margins in the Dowling-Meara derived cell line. Such delays in restoring the normal intermediate filament network after physiological processes involving cytoskeleton remodelling may render the cells vulnerable to cytolysis in vivo if physically challenged during this time window. The steady reduction in the mitotic index of the epidermis during the first few years of life could then explain the clinical improvement which is frequently observed in growing children.

Novel and recurrent mutations in keratinKRT5andKRT14genes in epidermolysis bullosa simplex: implications for disease phenotype and keratin filament assembly

2006 ◽  
Vol 27 (7) ◽  
pp. 719-720 ◽  
Author(s):  
Felix B. Müller ◽  
Wolfgang Küster ◽  
Kerstin Wodecki ◽  
Hiram Almeida ◽  
Leena Bruckner-Tuderman ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Disease Phenotype ◽  
Epidermolysis Bullosa Simplex ◽  
Filament Assembly ◽  
Recurrent Mutations ◽  
Keratin Filament
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