Special Issue "Plectin in Health and Disease"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Proliferation and Division".

Deadline for manuscript submissions: closed (31 July 2021).

Special Issue Editor

Dr. Gerhard Wiche
E-Mail Website
Guest Editor
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria

Special Issue Information

Dear Colleagues,

First identified in the early eighties, the intermediate filament (IF) linker protein plectin has emerged as a key player in cytoskeleton organization and dynamics. Owing to its structural diversity, functional versatility and broad interaction profile, it is involved in many fundamental cellular processes and plays an important role in human diseases. By networking IFs and targeting them to peripheral junctional complexes and internal organelles, plectin is crucial for the integrity and functionality of IF networks including cytoplasmic compartmentalization. Thus, in partnership with IFs, plectin affects the morphology and mechanical resilience of cells, the directionality of actomyosin-based contractile forces and the dynamics of micro­tubules, and it is involved in cellular signaling, especially mechanotransduction to the nucleus.

This special issue aims at presenting current status, recent developments, and future directions of plectin research with emphasis on the following topics:

  • Plectin as cytoskeleton organizer and mechanotransducer
  • Muscle-related plectinopathies
  • Neuromuscular synapse-related plectinopathies
  • Plectin in skin fragility disorders (EBS and paraneoplastic pemphigus)
  • Plectin in cancer with focus on its role i) as biomarker and therapeutic target and ii) in epithelial-mesenchymal transition (EMT)and tumor cell migration
  • Animal models to unveil physiological functions of plectin and disease mechanisms of plectinopathies
  • Genome-wide association studies (GWAS) revealing PLEC as osteoarthritis susceptibility gene
  • Plectin in the nervous system and a speculative role in brain astrocytes

Dr. Gerhard Wiche
Guest Editor

Manuscript Submission Information

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Keywords

  • plectin
  • cytolinkers
  • intermediate filaments
  • mechanotransduction
  • muscular dystrophies
  • skin fragilityl osteoarthritis
  • cancer

Published Papers (7 papers)

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Research

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Article
A Novel Monoclonal Antibody Targeting Cancer-Specific Plectin Has Potent Antitumor Activity in Ovarian Cancer
Cells 2021, 10(9), 2218; https://doi.org/10.3390/cells10092218 - 27 Aug 2021
Cited by 1 | Viewed by 439
Abstract
Cancer-specific plectin (CSP) is a pro-tumorigenic protein selectively expressed on the cell surface of major cancers, including ovarian cancer (OC). Despite its assessable localization, abundance, and functional significance, the therapeutic efficacy of targeting CSP remains unexplored. Here, we generated and investigated the anticancer [...] Read more.
Cancer-specific plectin (CSP) is a pro-tumorigenic protein selectively expressed on the cell surface of major cancers, including ovarian cancer (OC). Despite its assessable localization, abundance, and functional significance, the therapeutic efficacy of targeting CSP remains unexplored. Here, we generated and investigated the anticancer effects of a novel CSP-targeting monoclonal antibody, 1H11, in OC models. Its therapeutic efficacy as a monotherapy and in combination with chemotherapy was evaluated in vitro using two OC cell lines and in vivo by a subcutaneous ovarian cancer model. 1H11 demonstrated rapid internalization and high affinity and specificity for both human and murine CSP. Moreover, 1H11 induced significant and selective cytotoxicity (EC50 = 260 nM), G0/G1 arrest, and decreased OC cell migration. Mechanistically, these results are associated with increased ROS levels and reduced activation of the JAK2-STAT3 pathway. In vivo, 1H11 decreased Ki67 expression, induced 65% tumor growth inhibition, and resulted in 30% tumor necrosis. Moreover, 1H11 increased chemosensitivity to cisplatin resulting in 60% greater tumor growth inhibition compared to cisplatin alone. Taken together, CSP-targeting with 1H11 exhibits potent anticancer activity against ovarian cancer and is deserving of future clinical development. Full article
(This article belongs to the Special Issue Plectin in Health and Disease)
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Review

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Review
Plectin in Skin Fragility Disorders
Cells 2021, 10(10), 2738; https://doi.org/10.3390/cells10102738 - 14 Oct 2021
Viewed by 341
Abstract
Plectin is a multi-faceted, 500 kDa-large protein, which due to its expression in different isoforms and distinct organs acts diversely as a cytoskeletal crosslinker and signaling scaffold. It functions as a mediator of keratinocyte mechanical stability in the skin, primarily through linking intermediate [...] Read more.
Plectin is a multi-faceted, 500 kDa-large protein, which due to its expression in different isoforms and distinct organs acts diversely as a cytoskeletal crosslinker and signaling scaffold. It functions as a mediator of keratinocyte mechanical stability in the skin, primarily through linking intermediate filaments to hemidesmosomes. Skin fragility may occur through the presence of mutations in the gene encoding for plectin, PLEC, or through the presence of autoantibodies against the molecule. Below, we review the cutaneous manifestations of plectinopathies as well as their systemic involvement in specific disease subtypes. We summarize the known roles of plectin in keratinocytes and fibroblasts and provide an outlook on future perspectives for plectin-associated skin disorders. Full article
(This article belongs to the Special Issue Plectin in Health and Disease)
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Review
Muscle-Related Plectinopathies
Cells 2021, 10(9), 2480; https://doi.org/10.3390/cells10092480 - 19 Sep 2021
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Abstract
Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies. The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with [...] Read more.
Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies. The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness. Besides EBS-MD, PLEC mutations lead to EBS with nail dystrophy, EBS-MD with a myasthenic syndrome, EBS with pyloric atresia, limb-girdle muscular dystrophy type R17, or EBS-Ogna. In this review, we focus on the clinical and pathological manifestations caused by PLEC mutations on skeletal and cardiac muscle. Skeletal muscle biopsies from EBS-MD patients and plectin-deficient mice revealed severe dystrophic features with variation in fiber size, degenerative myofibrillar changes, mitochondrial alterations, and pathological desmin-positive protein aggregates. Ultrastructurally, PLEC mutations lead to a disorganization of myofibrils and sarcomeres, Z- and I-band alterations, autophagic vacuoles and cytoplasmic bodies, and misplaced and degenerating mitochondria. We also summarize a variety of genetically manipulated mouse and cell models, which are either plectin-deficient or that specifically lack a skeletal muscle-expressed plectin isoform. These models are powerful tools to study functional and molecular consequences of PLEC defects and their downstream effects on the skeletal muscle organization. Full article
(This article belongs to the Special Issue Plectin in Health and Disease)
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Review
Identifying Plectin Isoform Functions through Animal Models
Cells 2021, 10(9), 2453; https://doi.org/10.3390/cells10092453 - 17 Sep 2021
Viewed by 299
Abstract
Plectin, a high-molecular-weight cytoskeletal linker protein, binds with high affinity to intermediate filaments of all types and connects them to junctional complexes, organelles, and inner membrane systems. In addition, it interacts with actomyosin structures and microtubules. As a multifunctional protein, plectin has been [...] Read more.
Plectin, a high-molecular-weight cytoskeletal linker protein, binds with high affinity to intermediate filaments of all types and connects them to junctional complexes, organelles, and inner membrane systems. In addition, it interacts with actomyosin structures and microtubules. As a multifunctional protein, plectin has been implicated in several multisystemic diseases, the most common of which is epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). A great part of our knowledge about plectin’s functional diversity has been gained through the analysis of a unique collection of transgenic mice that includes a full (null) knockout (KO), several tissue-restricted and isoform-specific KOs, three double KOs, and two knock-in lines. The key molecular features and pathological phenotypes of these mice will be discussed in this review. In summary, the analysis of the different genetic models indicated that a functional plectin is required for the proper function of striated and simple epithelia, cardiac and skeletal muscle, the neuromuscular junction, and the vascular endothelium, recapitulating the symptoms of humans carrying plectin mutations. The plectin-null line showed severe skin and muscle phenotypes reflecting the importance of plectin for hemidesmosome and sarcomere integrity; whereas the ablation of individual isoforms caused a specific phenotype in myofibers, basal keratinocytes, or neurons. Tissue-restricted ablation of plectin rendered the targeted cells less resilient to mechanical stress. Studies based on animal models other than the mouse, such as zebrafish and C. elegans, will be discussed as well. Full article
(This article belongs to the Special Issue Plectin in Health and Disease)
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Review
Plectin in the Central Nervous System and a Putative Role in Brain Astrocytes
Cells 2021, 10(9), 2353; https://doi.org/10.3390/cells10092353 - 08 Sep 2021
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Abstract
Plectin, a high-molecular-mass cytolinker, is abundantly expressed in the central nervous system (CNS). Currently, a limited amount of data about plectin in the CNS prevents us from seeing the complete picture of how plectin affects the functioning of the CNS as a whole. [...] Read more.
Plectin, a high-molecular-mass cytolinker, is abundantly expressed in the central nervous system (CNS). Currently, a limited amount of data about plectin in the CNS prevents us from seeing the complete picture of how plectin affects the functioning of the CNS as a whole. Yet, by analogy to its role in other tissues, it is anticipated that, in the CNS, plectin also functions as the key cytoskeleton interlinking molecule. Thus, it is likely involved in signalling processes, thereby affecting numerous fundamental functions in the brain and spinal cord. Versatile direct and indirect interactions of plectin with cytoskeletal filaments and enzymes in the cells of the CNS in normal physiological and in pathologic conditions remain to be fully addressed. Several pathologies of the CNS related to plectin have been discovered in patients with plectinopathies. However, in view of plectin as an integrator of a cohesive mesh of cellular proteins, it is important that the role of plectin is also considered in other CNS pathologies. This review summarizes the current knowledge of plectin in the CNS, focusing on plectin isoforms that have been detected in the CNS, along with its expression profile and distribution alongside diverse cytoskeleton filaments in CNS cell types. Considering that the bidirectional communication between neurons and glial cells, especially astrocytes, is crucial for proper functioning of the CNS, we place particular emphasis on the known roles of plectin in neurons, and we propose possible roles of plectin in astrocytes. Full article
(This article belongs to the Special Issue Plectin in Health and Disease)
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Review
Plectin in Cancer: From Biomarker to Therapeutic Target
Cells 2021, 10(9), 2246; https://doi.org/10.3390/cells10092246 - 30 Aug 2021
Viewed by 522
Abstract
The cytolinker and scaffolding protein, plectin, has emerged as a potent driver of malignant hallmarks in many human cancers due to its involvement in various cellular activities contributing to tumorigenesis, including cancer cell proliferation, adhesion, migration, invasion, and signal transduction. Evidence shows that [...] Read more.
The cytolinker and scaffolding protein, plectin, has emerged as a potent driver of malignant hallmarks in many human cancers due to its involvement in various cellular activities contributing to tumorigenesis, including cancer cell proliferation, adhesion, migration, invasion, and signal transduction. Evidence shows that beyond plectin’s diverse protein interactome, its cancer-specific mislocalization to the cell surface enables its function as a potent oncoprotein. As such, therapeutic targeting of plectin, its protein interactors, and, in particular, cancer-specific plectin (CSP) presents an attractive opportunity to impede carcinogenesis directly. Here, we report on plectin’s differential gene and protein expression in cancer, explore its mutational profile, and discuss the current understanding of plectin’s and CSP’s biological function in cancer. Moreover, we review the landscape of plectin as a prognostic marker, diagnostic biomarker, and target for imaging and therapeutic modalities. We highlight how, beyond their respective biological importance, plectin’s common overexpression in cancer and CSP’s cancer-specific bioavailability underscore their potential as high-value druggable targets. We discuss how recent evidence of the potent anti-cancer effects of CSP therapeutic targeting opens the door for cell-surface mislocalized proteins as novel therapeutic targets. Full article
(This article belongs to the Special Issue Plectin in Health and Disease)
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Review
Plectin-Mediated Intermediate Filament Functions: Why Isoforms Matter
Cells 2021, 10(8), 2154; https://doi.org/10.3390/cells10082154 - 21 Aug 2021
Viewed by 505
Abstract
This essay focuses on the role of plectin and its various isoforms in mediating intermediate filament (IF) network functions. It is based on previous studies that provided comprehensive evidence for a concept where plectin acts as an IF recruiter, and plectin-mediated IF networking [...] Read more.
This essay focuses on the role of plectin and its various isoforms in mediating intermediate filament (IF) network functions. It is based on previous studies that provided comprehensive evidence for a concept where plectin acts as an IF recruiter, and plectin-mediated IF networking and anchoring are key elements in IF function execution. Here, plectin’s global role as modulator of IF functionality is viewed from different perspectives, including the mechanical stabilization of IF networks and their docking platforms, contribution to cellular viscoelasticity and mechanotransduction, compartmentalization and control of the actomyosin machinery, connections to the microtubule system, and mechanisms and specificity of isoform targeting. Arguments for IF networks and plectin acting as mutually dependent partners are also given. Lastly, a working model is presented that describes a unifying mechanism underlying how plectin–IF networks mechanically control and propagate actomyosin-generated forces, affect microtubule dynamics, and contribute to mechanotransduction. Full article
(This article belongs to the Special Issue Plectin in Health and Disease)
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