Plectin and its isoforms are versatile cytoskeletal linker proteins of very large size (>500 kDa) that are abundantly expressed in a wide variety of mammalian tissues and cell types. Earlier studies indicated that plectin molecules were associated with and/or directly bound to subcomponents of all three major cytoskeletal filament networks, the subplasma membrane protein skeleton, and a variety of plasma membrane-cytoskeleton junctional complexes, including those found in epithelia, various types of muscle, and fibroblasts. In conjunction with biochemical data, this led to the concept that plectin plays an important role in cytoskeleton network organization, with consequences for viscoelastic properties of the cytoplasm and the mechanical integrity and resistance of cells and tissues. Several recent findings lent strong support to this concept. One was that a hereditary disease, epidermolysis bullosa simplex (EBS)MD, characterized by severe skin blistering combined with muscular dystrophy, is caused by defects in the plectin gene. Another was the generation of plectin-deficient mice by targeted inactivation of the gene. Dying shortly after birth, these animals exhibited severe defects in skin, skeletal muscle and heart. Moreover, in vitro studies with cells derived from such animals unmasked an essential new role of plectin as regulator of cellular processes involving actin stress fibers dynamics. Comprehensive analyses of the gene locus in man, mouse, and rat point towards a complex gene expression machinery, comprising an unprecedented diversity of differentially spliced transcripts with distinct 5 ′ starting exons, probably regulated by different promoters. This could provide a basis for cell type-dependent and/or developmentally-controlled expression of plectin isoforms, exerting different functions through binding to distinct partners. Based on its versatile functions and structural diversification plectin emerges as a prototype cytolinker protein among a family of proteins sharing partial structural homology and functions. SUMMARY

COMMENTARY Role of plectin in cytoskeleton organization and dynamics

Based upon case reports and small case series, it has been known for many years that some types and subtypes of inherited epidermolysis bullosa (EB) may be at risk for developing one or more extracutaneous complications. Many of these are associated with considerable morbidity; some may result in death. Only over the past few years have there been data generated from large, well characterized cohorts. However, these data, to date, have been published almost exclusively in the nondermatologic literature. Our objective is to provide dermatologists with a comprehensive review of each major extracutaneous complication with a summary of the pertinent literature and recommendations for evaluation and optimal management. Part I highlights epithelial associated tissues, and part II addresses other organs. Based on these reviews, the readership should gain a greater understanding of the types of complications that may occur, when they are most likely to develop, and the range of medical and surgical interventions that are currently available. It should also be possible for the reader to develop surveillance strategies based on an understanding of the published evidence-based data. The breadth and range of severity of complications that arise in some EB types and subtypes within the external eye, ear, nose, upper airway, and gastrointestinal and genitourinary tracts suggest that optimal management must be multidisciplinary. Given the unique knowledge that dermatologists have of this disease, we believe that the care of the EB patient should be under the direction of his or her dermatologist, who can best assist in timely referrals to those specialists who are most experienced in the care of specific extracutaneous problems.

https://www.jaad.org/article/S0190-9622(09)00705-1/pdf

Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues.

Plectin, a major linker and scaffolding protein of the cytoskeleton, has been shown to be essential for the mechanical integrity of skin, skeletal muscle, and heart. Studying fibroblast and astroglial cell cultures derived from plectin (−/−) mice, we found that their actin cytoskeleton, including focal adhesion contacts, was developed more extensively than in wild-type cells. Also it failed to show characteristic short-term rearrangments in response to extracellular stimuli activating the Rho/Rac/Cdc42 signaling cascades. As a consequence, cell motility, adherence, and shear stress resistance were altered, and morphogenic processes were delayed. Furthermore, we show that plectin interacts with G-actin in vitro in a phosphatidylinositol-4,5-biphosphate-dependent manner and associates with actin stress fibers in living cells. The actin stress fiber phenotype of plectin-deficient fibroblasts could be reversed to a large degree by transient transfection of full-length plectin or plectin fragments containing the amino-terminal actin-binding domain (ABD). These results reveal a novel role of plectin as regulator of cellular processes involving actin filament dynamics that goes beyond its proposed role in scaffolding and mechanical stabilization of cells.

/pdf/not-just-scaffolding-plectin-regulates-actin-dynamics-in-a901nwcfh3.pdf

Not just scaffolding: plectin regulates actin dynamics in cultured cells

Plectin, the most versatile cytolinker identified to date, has essential functions in maintaining the mechanical integrity of skin, skeletal muscle and heart, as indicated by analyses of plectin-deficient mice and humans. Expression of plectin in a vast variety of tissues and cell types, combined with a large number of different binding partners identified at the molecular level, calls for complex mechanisms regulating gene transcription and expression of the protein. To investigate these mechanisms, we analyzed the transcript diversity and genomic organization of the murine plectin gene and found a remarkable complexity of its 5'-end structure. An unusually high number of 14 alternatively spliced exons, 11 of them directly splicing into plectin exon 2, were identified. Analysis of their tissue distribution revealed that expression of a few of them is restricted to tissues such as brain, or skeletal muscle and heart. In addition, we found two short exons tissue-specifically spliced into a highly conserved set of exons encoding the N-terminal actin binding domain (ABD), common to plectin and the superfamily of spectrin/dystrophin-type actin binding proteins. Using recombinant proteins we show that a novel ABD version contained in the muscle-specific isoform of plectin exhibits significantly higher actin binding activity than other splice forms. This fine tuning mechanism based on alternative splicing is likely to optimize the proposed biological role of plectin as a cytolinker opposing intense mechanical forces in tissues like striated muscle.

Unusual 5′ Transcript Complexity of Plectin Isoforms: Novel Tissue-Specific Exons Modulate Actin Binding Activity

Plectin, a giant multifunctional cytolinker protein, plays a crucial role in stabilizing and orchestrating intermediate filament networks in cells. Mutations in the human plectin gene result in multiple diseases manifesting with muscular dystrophy, skin blistering, and signs of neuropathy. The most common disease caused by plectin deficiency is epidermolysis bullosa simplex (EBS)-MD, a rare autosomal-recessive skin blistering disorder with late-onset muscular dystrophy. EBS-MD patients and plectin-deficient mice display pathologic desmin-positive protein aggregates, degenerated myofibrils, and mitochondrial abnormalities, the hallmarks of myofibrillar myopathies. In addition to EBS-MD, plectin mutations have been shown to cause EBS-MD with a myasthenic syndrome, limb-girdle muscular dystrophy type 2Q, EBS with pyloric atresia, and EBS-Ogna. This review focuses on clinical and pathological manifestations of these plectinopathies. It addresses especially plectin’s role in skeletal muscle, where a loss of muscle fiber integrity and profound changes of myofiber cytoarchitecture are observed in its absence. Furthermore, the highly complex genetic and molecular structure of plectin is discussed; a high number of differentially spliced exons give rise to a variety of different isoforms, which fulfill distinct functions in different cell types and tissues. Plectin’s abilities to act as a dynamic organizer of intermediate filament networks and to interact with a multitude of different interaction partners are the basis for its function as a scaffolding platform for proteins involved in signaling. Finally, the article addresses a series of genetically manipulated mouse lines that were generated to serve as powerful models to study functional and molecular consequences of plectin gene defects.

The many faces of plectin and plectinopathies: pathology and mechanisms.

Summary

Plectin is a 500kDa protein involved in cytoskeleton-plasma membrane attachment with a wide tissue distribution including cutaneous and airway epithelia, muscle and neuronal tissue. Recently, mutations in the gene encoding plectin (PLECI) have been implicated in the pathogenesis of an autosomal recessive variant of epidermolysis bullosa simplex in which cutaneous blistering starting in the neonatal period is associated with muscular dystrophy in later life. In this study, we report two unrelated patients, both of consanguineous parentage, who presented with cutaneous blistering and a hoarse cry from birth. Both experienced inspiratory stridor and respiratory distress, necessitating emergency tracheostomy in one case. Immunoreactivity to monoclonal antibodies against plectin was absent or markedly reduced in skin biopsies from both patients. Electron microscopy revealed a low intraepidermal plane of cleavage and hypoplastic hemidesmosomes with a reduced association with keratin intermediate filaments. Direct sequencing of PLEC1 in each case demonstrated two novel homozygous frameshift deletion mutations. 5069del19 and 5905del2, which both create downstream premature termination codons. Although currently neither patient has symptoms of muscle disease, the identification of mutations in PLEC1 may be predictive for the future development of muscular dystrophy. Recessive epidermolysis bullosa simplex resulting form abnormalities in plectin should be considered in the differential diagnosis of cutaneous blistering, hoarseness and stridor in infancy.

Recessive epidermolysis bullosa simplex associated with plectin mutations: infantile respiratory complications in two unrelated cases.

Recessive epidermolysis bullosa simplex with respiratory complications caused by mutations in the plectin gene

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

G. A. J. Morrison

Author Tools

Chat about Author

Papers

Recessive epidermolysis bullosa simplex associated with plectin mutations: infantile respiratory complications in two unrelated cases.

Recessive epidermolysis bullosa simplex with respiratory complications caused by mutations in the plectin gene