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From Keratin Mutation Disorders to Their Structural Biology and Human Pathology Applications

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 17738

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Dr. Alessandro Terrinoni

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Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
Interests: keratinocyte; skin differentiation; genodermatosis; psoriasis
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Dear Colleagues,

The disorders of keratinization (DOKs) are genetic defects characterized by a variety of clinical symptoms and histological features, including in many cases thickened stratum corneum and scaling skin. They can be severely debilitating diseases, though rarely lethal, with an incidence between 1:100.000 and 1:300.000. Many molecular genetic defects of these inherited skin diseases have been characterized in the last decade.

The genetic mutations in keratin genes lead to errors during the complex assembly and differentiation process of the epidermis, leading to keratin-associated skin diseases. This is because the cytoskeletal system of keratin intermediate filaments (KIFs) is fundamental in the cytoplasm of keratinocytes. This system is composed of unbranched filaments of ~10 nm in diameter which are chemically stable, confer to cells and skin mechanical resistance, and have a barrier function.

The keratin gene family contains a high number of members, with 54 unic functional genes having been detected in humans. Keratins proteins are expressed in keratinocytes as heterodimers of two main families, located in two different chromosomal loci: the type I genes on chromosome 17q21.2, and those encoding type II keratins on chromosome 12q13.13. Additional association of the initial heterodimer gives rise to the filament of ~10 nm. Further modifications, including crosslinking between filament, will generate the functional cytoskeleton of keratinocytes. During the differentiation of the epidermis, keratin dimers are expressed in a stratum and tissue specific fashion. The resulting phenotype of mutations in keratin genes is specific for the type, the localization, and the role of the keratin involved. Moreover, the availability of structural data is now revealing the biochemical behavior of the mutations, elucidating the biological role of these proteins in the pathophysiology of the diseases, and in other aspects of keratinocytes’ cellular biology. Research papers, up-to-date review articles, and commentaries are all welcome.

Dr. Alessandro Terrinoni
Guest Editor

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Keywords

keratins
mutations
keratin structural domains
ichthyosis
epidermolysis
erithrodermia

Published Papers (6 papers)

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Research

16 pages, 2592 KiB

Open AccessArticle

First Case of KRT2 Epidermolytic Nevus and Novel Clinical and Genetic Findings in 26 Italian Patients with Keratinopathic Ichthyoses

by Andrea Diociaiuti, Daniele Castiglia, Marialuisa Corbeddu, Roberta Rotunno, Sabrina Rossi, Elisa Pisaneschi, Claudia Cesario, Angelo Giuseppe Condorelli, Giovanna Zambruno and May El Hachem

Int. J. Mol. Sci. 2020, 21(20), 7707; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207707 - 18 Oct 2020

Cited by 8 | Viewed by 2407

Abstract

Keratinopathic ichthyoses (KI) are a clinically heterogeneous group of keratinization disorders due to mutations in KRT1, KTR10, or KRT2 genes encoding keratins of suprabasal epidermis. Characteristic clinical features include superficial blisters and erosions in infancy and progressive development of hyperkeratosis. Histopathology shows epidermolytic hyperkeratosis. We describe the clinical, histopathological, and molecular findings of a series of 26 Italian patients from 19 unrelated families affected with (i) epidermolytic ichthyosis due to KRT1 or KRT10 mutations (7 and 9 cases, respectively); (ii) KTR10-mutated ichthyosis with confetti (2 cases); (iii) KRT2-mutated superficial epidermolytic ichthyosis (5 cases); and (iv) KRT10-mutated epidermolytic nevus (2 cases). Of note, molecular genetic testing in a third case of extensive epidermolytic nevus revealed a somatic missense mutation (p.Asn186Asp) in the KRT2 gene, detected in DNA from lesional skin at an allelic frequency of 25% and, at very low frequency (1.5%), also in blood. Finally, we report three novel dominant mutations, including a frameshift mutation altering the C-terminal V2 domain of keratin 1 in three familiar cases presenting a mild phenotype. Overall, our findings expand the phenotypic and molecular spectrum of KI and show for the first time that epidermolytic nevus can be due to somatic KRT2 mutation. Full article

(This article belongs to the Special Issue From Keratin Mutation Disorders to Their Structural Biology and Human Pathology Applications)

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14 pages, 1807 KiB

Open AccessArticle

Molecular Modeling of Pathogenic Mutations in the Keratin 1B Domain

by Alexander J. Hinbest, Sherif A. Eldirany, Minh Ho and Christopher G. Bunick

Int. J. Mol. Sci. 2020, 21(18), 6641; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186641 - 10 Sep 2020

Cited by 6 | Viewed by 3065

Abstract

Keratin intermediate filaments constitute the primary cytoskeletal component of epithelial cells. Numerous human disease phenotypes related to keratin mutation remain mechanistically elusive. Our recent crystal structures of the helix 1B heterotetramer from keratin 1/10 enabled further investigation of the effect of pathologic 1B domain mutations on keratin structure. We used our highest resolution keratin 1B structure as a template for homology-modeling the 1B heterotetramers of keratin 5/14 (associated with blistering skin disorders), keratin 8/18 (associated with liver disease), and keratin 74/28 (associated with hair disorder). Each structure was examined for the molecular alterations caused by incorporating pathogenic 1B keratin mutations. Structural modeling indicated keratin 1B mutations can harm the heterodimer interface (R265P^K5, L311R^K5, R211P^K14, I150V^K18), the tetramer interface (F231L^K1, F274S^K74), or higher-order interactions needed for mature filament formation (S233L^K1, L311R^K5, Q169E^K8, H128L^K18). The biochemical changes included altered hydrophobic and electrostatic interactions, and altered surface charge, hydrophobicity or contour. Together, these findings advance the genotype-structurotype-phenotype correlation for keratin-based human diseases. Full article

(This article belongs to the Special Issue From Keratin Mutation Disorders to Their Structural Biology and Human Pathology Applications)

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11 pages, 2254 KiB

Open AccessArticle

A Simple Method for the Production of Human Skin Equivalent in 3D, Multi-Cell Culture

by Łukasz Szymański, Krystyna Jęderka, Aleksandra Cios, Martyna Ciepelak, Aneta Lewicka, Wanda Stankiewicz and Sławomir Lewicki

Int. J. Mol. Sci. 2020, 21(13), 4644; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134644 - 30 Jun 2020

Cited by 18 | Viewed by 4452

Abstract

An important problem for researchers working in the field of dermatology is the preparation of the human skin equivalent (HSE). Here, we describe a simple and reliable protocol for preparing a skin model from the commercially available cell lines: keratinocytes, fibroblasts, and melanocytes. Importantly, in our 3D model, the keratinocytes are diverse that brings this model closer to the natural skin. For the production of HSE, we used available primary PCS-200-010, PCS-201-010, PCS-200-013, and immortalized CRL-4048 and CRL-4001 cell lines. We used genipin, which is necessary for collagen cross-linking and studied its cytotoxicity for keratinocytes and fibroblasts. The addition of 20 μM genipin reduced the shrinkage of the collagen in the constructs from 59% to 24% on day 12 of the culture of the construct. A higher concentration (80–200 µM) of genipin reduced shrinkage by 14% on average. Genipin in concentration 10 μM and below was not cytotoxic to the keratinocytes, and 150 μM and below to the fibroblasts. Hematoxylin and eosin staining showed that the morphology of HSEs was identical to that of native human skin. The immunohistochemical staining of the constructs showed the presence of vimentin-positive fibroblasts in the skin layer, while the melanocytes were in the epidermis and in the basal layer. We observed that the longer differentiation of constructs led to the higher secretion of GM-CSF, IL-10, IL-15, IL-1α, IL-6, IL-7, IL-8, and MCP-1. We also observed that the longer time of differentiation led to a more stable secretion of all analytes, which was reflected in the coefficient of variation. We described here a simple, reliable, and cost-effective production of the full-thickness human skin equivalents that can be used in the research and industry. With the global trend to decrease animal use for the research and testing, our HSE could be a useful testing tool and an alternative research model. Full article

(This article belongs to the Special Issue From Keratin Mutation Disorders to Their Structural Biology and Human Pathology Applications)

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15 pages, 2413 KiB

Open AccessArticle

Analysis of Spatial Distribution and Prognostic Value of Different Pan Cytokeratin Immunostaining Intensities in Breast Tumor Tissue Sections

by Velicko Vranes, Tijana Vujasinović, Nemanja Rajković, Ksenija Kanjer, Nebojša T. Milošević and Marko Radulovic

Int. J. Mol. Sci. 2020, 21(12), 4434; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124434 - 22 Jun 2020

Cited by 3 | Viewed by 1809

Abstract

Cancer risk prognosis could improve patient survival through early personalized treatment decisions. This is the first systematic analysis of the spatial and prognostic distribution of different pan cytokeratin immunostaining intensities in breast tumors. The prognostic model included 102 breast carcinoma patients, with distant metastasis occurrence as the endpoint. We segmented the full intensity range (0–255) of pan cytokeratin digitized immunostaining into seven discrete narrow grey level ranges: 0–130, 130–160, 160–180, 180–200, 200–220, 220–240, and 240–255. These images were subsequently examined by 33 major (GLCM), fractal and first-order statistics computational analysis features. Interestingly, while moderate intensities were strongly associated with metastasis outcome, high intensities of pan cytokeratin immunostaining provided no prognostic value even after an exhaustive computational analysis. The intense pan cytokeratin immunostaining was also relatively rare, suggesting the low differentiation state of epithelial cells. The observed variability in immunostaining intensities highlighted the intratumoral heterogeneity of the malignant cells and its association with a poor disease outcome. The prognostic importance of the moderate intensity range established by complex computational morphology analyses was supported by simple measurements of its immunostaining area which was associated with favorable disease outcome. This study reveals intratumoral heterogeneity of the pan cytokeratin immunostaining together with the prognostic evaluation and spatial distribution of its discrete intensities. Full article

(This article belongs to the Special Issue From Keratin Mutation Disorders to Their Structural Biology and Human Pathology Applications)

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21 pages, 5572 KiB

Open AccessArticle

Leukamenin E Induces K8/18 Phosphorylation and Blocks the Assembly of Keratin Filament Networks Through ERK Activation

by Bo Xia, Hui Zhang, Minghui Yang, Shilong Du, Jingxin Wei and Lan Ding

Int. J. Mol. Sci. 2020, 21(9), 3164; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093164 - 30 Apr 2020

Cited by 2 | Viewed by 2593

Abstract

Leukamenin E is a natural ent-kaurane diterpenoid isolated from Isodon racemosa (Hemsl) Hara that has been found to be a novel and potential keratin filament inhibitor, but its underlying mechanisms remain largely unknown. Here, we show that leukamenin E induces keratin filaments (KFs) depolymerization, largely independently of microfilament (MFs) and microtubules (MTs) in well-spread cells and inhibition of KFs assembly in spreading cells. These effects are accompanied by keratin phosphorylation at K8-Ser73/Ser431 and K18-Ser52 via the by extracellular signal-regulated kinases (ERK) pathway in primary liver carcinoma cells (PLC) and human umbilical vein endothelial cells (HUVECs). Moreover, leukamenin E increases soluble pK8-Ser73/Ser431, pK18-Ser52, and pan-keratin in the cytoplasmic supernatant by immunofluorescence imaging and Western blotting assay. Accordingly, leukamenin E inhibits the spreading and migration of cells. We propose that leukamenin E-induced keratin phosphorylation may interfere with the initiation of KFs assembly and block the formation of a new KFs network, leading to the inhibition of cell spreading. Leukamenin E is a potential target drug for inhibition of KFs assembly. Full article

(This article belongs to the Special Issue From Keratin Mutation Disorders to Their Structural Biology and Human Pathology Applications)

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14 pages, 2507 KiB

Open AccessArticle

Keratin Dynamics and Spatial Distribution in Wild-Type and K14 R125P Mutant Cells—A Computational Model

by Marcos Gouveia, Špela Zemljič-Jokhadar, Marko Vidak, Biljana Stojkovič, Jure Derganc, Rui Travasso and Mirjana Liovic

Int. J. Mol. Sci. 2020, 21(7), 2596; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072596 - 09 Apr 2020

Cited by 3 | Viewed by 2990

Abstract

Keratins are one of the most abundant proteins in epithelial cells. They form a cytoskeletal filament network whose structural organization seriously conditions its function. Dynamic keratin particles and aggregates are often observed at the periphery of mutant keratinocytes related to the hereditary skin disorder epidermolysis bullosa simplex, which is due to mutations in keratins 5 and 14. To account for their emergence in mutant cells, we extended an existing mathematical model of keratin turnover in wild-type cells and developed a novel 2D phase-field model to predict the keratin distribution inside the cell. This model includes the turnover between soluble, particulate and filamentous keratin forms. We assumed that the mutation causes a slowdown in the assembly of an intermediate keratin phase into filaments, and demonstrated that this change is enough to account for the loss of keratin filaments in the cell’s interior and the emergence of keratin particles at its periphery. The developed mathematical model is also particularly tailored to model the spatial distribution of keratins as the cell changes its shape. Full article

(This article belongs to the Special Issue From Keratin Mutation Disorders to Their Structural Biology and Human Pathology Applications)

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