The rod domain is not essential for the function of plectin in maintaining tissue integrity

Ketema, Mirjam; Secades, Pablo; Kreft, Maaike; Nahidiazar, Leila; Janssen, Hans; Jalink, Kees; Pereda, José M. de; Sonnenberg, Arnoud

doi:10.1091/mbc.e15-01-0043

Cited by 21 publications

(26 citation statements)

References 61 publications

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“…5B). Previous studies have demonstrated low nesprin-3 expression within the epidermis, and mice lacking nesprin-3 have a normal skin phenotype (Ketema et al, 2013). These findings suggest that in keratinocytes, plectin and nesprin-3 do not directly link keratins to the nuclear membrane.…”

Section: Resultsmentioning

confidence: 80%

The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes

Almeida

Walko

McMillan

et al. 2015

Journal of Cell Science

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The transmission of mechanical forces to the nucleus is important for intracellular positioning, mitosis and cell motility, yet the contribution of specific components of the cytoskeleton to nuclear mechanotransduction remains unclear. In this study, we examine how crosstalk between the cytolinker plectin and F-actin controls keratin network organisation and the 3D nuclear morphology of keratinocytes. Using micro-patterned surfaces to precisely manipulate cell shape, we find that cell adhesion and spreading regulate the size and shape of the nucleus. Disruption of the keratin cytoskeleton through loss of plectin facilitated greater nuclear deformation, which depended on actomyosin contractility. Nuclear morphology did not depend on direct linkage of the keratin cytoskeleton with the nuclear membrane, rather loss of plectin reduced keratin filament density around the nucleus. We further demonstrate that keratinocytes have abnormal nuclear morphologies in the epidermis of plectin-deficient, epidermolysis bullosa simplex patients. Taken together, our data demonstrate that plectin is an essential regulator of nuclear morphology in vitro and in vivo and protects the nucleus from mechanical deformation.

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Section: Resultsmentioning

confidence: 80%

The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes

Almeida

Walko

McMillan

et al. 2015

Journal of Cell Science

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“…The gene sequences encoding these eight isoforms 1, 1a, 1b, 1c, 1d, 1e, 1f, and 1g differ in their first exons and the corresponding upstream regulatory sequences (Fuchs et al, 1999;Rezniczek et al, 2003). Additionally, alternative splicing of exon 31 results in a rodless plectin variant, which has been identified in human keratinocytes and skeletal muscle plectin (Ketema et al, 2015;Winter and Wiche, 2013).…”

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confidence: 99%

A PLEC Isoform Identified in Skin, Muscle, and Heart

Gostyńska

Lemmink

Bremer

et al. 2017

Journal of Investigative Dermatology

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mediated by antibodies against thymusindependent carbohydrate antigen, for example, mismatched ABO antigen, and activated macrophages (Takahashi, 2005). Our HF allograft model is suitable for transplantation research, relatively easy to evaluate and more applicable to clinical studies, unlike solid organ transplantation. We found that MD-3 pretreatment enhanced HF allograft survival by significantly reducing alloreactive T-cell infiltration. The induction of antigen-specific T-cell tolerance by MD-3 could be adopted in the skin immune system and could be a potent therapeutic tool for preventing allograft rejection.

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“…A central rod domain (ϳ1250 amino acids) is responsible for homodimerization via coiled-coil interactions. Most of the rod domain is absent in a natural rod-less splice variant that retains the function of the full-length protein (11). Finally, the C-terminal region contains six plakin repeat domains and mediates binding to IFs (12).…”

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confidence: 99%

The Structure of the Plakin Domain of Plectin Reveals an Extended Rod-like Shape

Ortega

Manso

Buey

et al. 2016

Journal of Biological Chemistry

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Plakins are large multi-domain proteins that interconnect cytoskeletal structures. Plectin is a prototypical plakin that tethers intermediate filaments to membrane-associated complexes. Most plakins contain a plakin domain formed by up to nine spectrin repeats (SR1-SR9) and an SH3 domain. The plakin domains of plectin and other plakins harbor binding sites for junctional proteins. We have combined x-ray crystallography with small angle x-ray scattering (SAXS) to elucidate the structure of the plakin domain of plectin, extending our previous analysis of the SR1 to SR5 region. Two crystal structures of the SR5-SR6 region allowed us to characterize its uniquely wide inter-repeat conformational variability. We also report the crystal structures of the SR7-SR8 region, refined to 1.8 Å, and the SR7-SR9 at lower resolution. The SR7-SR9 region, which is conserved in all other plakin domains, forms a rigid segment stabilized by uniquely extensive inter-repeat contacts mediated by unusually long helices in SR8 and SR9. Using SAXS we show that in solution the SR3-SR6 and SR7-SR9 regions are rod-like segments and that SR3-SR9 of plectin has an extended shape with a small central kink. Other plakins, such as bullous pemphigoid antigen 1 and microtubule and actin cross-linking factor 1, are likely to have similar extended plakin domains. In contrast, desmoplakin has a two-segment structure with a central flexible hinge. The continuous versus segmented structures of the plakin domains of plectin and desmoplakin give insight into how different plakins might respond to tension and transmit mechanical signals.Plakins are a family of very large proteins that interconnect and organize the intermediate filaments (IF), 4 microtubules, and microfilaments of the cytoskeleton and tether them to membrane-associated structures (1, 2). So far, seven plakins have been described in mammals; these are plectin, bullous pemphigoid antigen 1 (BPAG1), desmoplakin, microtubule and actin cross-linking factor 1 (MACF1, also known as ACF7), envoplakin, periplakin, and epiplakin. Invertebrates have a more reduced plakin repertoire; for example Caenorhabditis elegans and Drosophila melanogaster each have a single plakin gene encoding VAB-10 and Shot (also known as Short Stop or kakapo), respectively. Most of the plakin genes produce multiple isoforms that increase the structural and functional versatility of these proteins.Plectin is expressed in a large variety of cell types in which it acts as a highly polyvalent cytolinker that contributes to cell adhesion and the organization of the cytoskeleton. Plectin cross-links IFs to microtubules and actin filaments and mediates the attachment of IFs to cell-cell and cell-matrix junctional complexes such as hemidesmosomes, desmosomes, Z-lines, and focal contacts. Plectin also connects IFs to organelles such as the nucleus and mitochondria (3). Defects in the PLEC gene cause various forms of the blistering disease epidermolysis bullosa simplex (EBS), which may occur only with skin fragility, as found in EBS Og...

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The rod domain is not essential for the function of plectin in maintaining tissue integrity

Abstract: Plectin is a cytoskeletal linker protein that consists of a central rod domain connecting two globular domains. Rodless plectin is able to functionally compensate for the loss of full-length plectin in mice and, like full-length plectin, is able to form dimers.

Cited by 21 publications

References 61 publications

The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes

The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes

A PLEC Isoform Identified in Skin, Muscle, and Heart

The Structure of the Plakin Domain of Plectin Reveals an Extended Rod-like Shape

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