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Open AccessEditorial

Plectin in Health and Disease

by Gerhard Wiche

Cells 2022, 11(9), 1412; https://doi.org/10.3390/cells11091412 - 21 Apr 2022

Cited by 1 | Viewed by 1475

Abstract

In light of recent progress in defining a unifying mechanism for the versatile functions and disease involvement of the cytolinker protein plectin, a series of invited review articles, together with an original research article, were published in Cells as a Special Issue entitled [...] Read more.

In light of recent progress in defining a unifying mechanism for the versatile functions and disease involvement of the cytolinker protein plectin, a series of invited review articles, together with an original research article, were published in Cells as a Special Issue entitled ‘Plectin in Health and Disease’ [...] Full article

(This article belongs to the Special Issue Plectin in Health and Disease)

Research

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25 pages, 10769 KiB

Open AccessArticle

Z-Disk-Associated Plectin (Isoform 1d): Spatial Arrangement, Interaction Partners, and Role in Filamin C Homeostasis

by Lilli Winter, Ilona Staszewska-Daca, Stefan Zittrich, Fatiha Elhamine, Michaela M. Zrelski, Katy Schmidt, Irmgard Fischer, Christian Jüngst, Astrid Schauss, Wolfgang H. Goldmann, Robert Stehle and Gerhard Wiche

Cells 2023, 12(9), 1259; https://doi.org/10.3390/cells12091259 - 26 Apr 2023

Cited by 2 | Viewed by 1525 | Correction

Abstract

Plectin, a highly versatile cytolinker protein, is crucial for myofiber integrity and function. Accordingly, mutations in the human gene (PLEC) cause several rare diseases, denoted as plectinopathies, with most of them associated with progressive muscle weakness. Of several plectin isoforms expressed [...] Read more.

Plectin, a highly versatile cytolinker protein, is crucial for myofiber integrity and function. Accordingly, mutations in the human gene (PLEC) cause several rare diseases, denoted as plectinopathies, with most of them associated with progressive muscle weakness. Of several plectin isoforms expressed in skeletal muscle and the heart, P1d is the only isoform expressed exclusively in these tissues. Using high-resolution stimulated emission depletion (STED) microscopy, here we show that plectin is located within the gaps between individual α-actinin-positive Z-disks, recruiting and bridging them to desmin intermediate filaments (Ifs). Loss of plectin in myofibril bundles led to a complete loss of desmin Ifs. Loss of Z-disk-associated plectin isoform P1d led to disorganization of muscle fibers and slower relaxation of myofibrils upon mechanical strain, in line with an observed inhomogeneity of muscle ultrastructure. In addition to binding to α-actinin and thereby providing structural support, P1d forms a scaffolding platform for the chaperone-assisted selective autophagy machinery (CASA) by directly interacting with HSC70 and synpo2. In isoform-specific knockout (P1d-KO) mouse muscle and mechanically stretched plectin-deficient myoblasts, we found high levels of undigested filamin C, a bona fide substrate of CASA. Similarly, subjecting P1d-KO mice to forced swim tests led to accumulation of filamin C aggregates in myofibers, highlighting a specific role of P1d in tension-induced proteolysis activated upon high loads of physical exercise and muscle contraction. Full article

(This article belongs to the Special Issue Plectin in Health and Disease)

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20 pages, 5095 KiB

Open AccessArticle

A Novel Monoclonal Antibody Targeting Cancer-Specific Plectin Has Potent Antitumor Activity in Ovarian Cancer

by Samantha M. Perez, Julien Dimastromatteo, Charles N. Landen, Jr. and Kimberly A. Kelly

Cells 2021, 10(9), 2218; https://doi.org/10.3390/cells10092218 - 27 Aug 2021

Cited by 7 | Viewed by 3552

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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8 pages, 1348 KiB

Open AccessReview

Plectin in Skin Fragility Disorders

by Dimitra Kiritsi, Leonidas Tsakiris and Franziska Schauer

Cells 2021, 10(10), 2738; https://doi.org/10.3390/cells10102738 - 14 Oct 2021

Cited by 7 | Viewed by 2596

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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21 pages, 4668 KiB

Open AccessReview

Muscle-Related Plectinopathies

by Michaela M. Zrelski, Monika Kustermann and Lilli Winter

Cells 2021, 10(9), 2480; https://doi.org/10.3390/cells10092480 - 19 Sep 2021

Cited by 14 | Viewed by 3591

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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22 pages, 1396 KiB

Open AccessFeature PaperReview

Identifying Plectin Isoform Functions through Animal Models

by Maria J. Castañón and Gerhard Wiche

Cells 2021, 10(9), 2453; https://doi.org/10.3390/cells10092453 - 17 Sep 2021

Cited by 9 | Viewed by 3078

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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18 pages, 1414 KiB

Open AccessReview

Plectin in the Central Nervous System and a Putative Role in Brain Astrocytes

by Maja Potokar and Jernej Jorgačevski

Cells 2021, 10(9), 2353; https://doi.org/10.3390/cells10092353 - 8 Sep 2021

Cited by 10 | Viewed by 2468

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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26 pages, 12229 KiB

Open AccessReview

Plectin in Cancer: From Biomarker to Therapeutic Target

by Samantha M. Perez, Lindsey T. Brinton and Kimberly A. Kelly

Cells 2021, 10(9), 2246; https://doi.org/10.3390/cells10092246 - 30 Aug 2021

Cited by 18 | Viewed by 4553

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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21 pages, 1473 KiB

Open AccessFeature PaperReview

Plectin-Mediated Intermediate Filament Functions: Why Isoforms Matter

by Gerhard Wiche

Cells 2021, 10(8), 2154; https://doi.org/10.3390/cells10082154 - 21 Aug 2021

Cited by 17 | Viewed by 4814

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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2 pages, 192 KiB

Open AccessCorrection

Correction: Winter et al. Z-Disk-Associated Plectin (Isoform 1d): Spatial Arrangement, Interaction Partners, and Role in Filamin C Homeostasis. Cells 2023, 12, 1259

by Lilli Winter, Ilona Staszewska-Daca, Stefan Zittrich, Fatiha Elhamine, Michaela M. Zrelski, Katy Schmidt, Irmgard Fischer, Christian Jüngst, Astrid Schauss, Wolfgang H. Goldmann, Robert Stehle and Gerhard Wiche

Cells 2023, 12(23), 2677; https://doi.org/10.3390/cells12232677 - 22 Nov 2023

Viewed by 466

Abstract

The authors wish to make the following changes to their paper [...] Full article

(This article belongs to the Special Issue Plectin in Health and Disease)

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