Remodeling of keratin-coupled cell adhesion complexes

Osmani, Naël; Labouesse, Michel

doi:10.1016/j.ceb.2014.10.004

Cited by 35 publications

(42 citation statements)

References 93 publications

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“…In addition, p38MAPK signaling promotes Dsg3 internalization which also may be a consequence of keratin uncoupling from desmosomes because a desmoplakin variant with stronger keratin insertion reduces desmosomal Dsg3 depletion . Thus, normal keratin coupling appears to be a central mechanism to maintain cell cohesion, which is not surprising given the crucial role of keratin filaments for epidermal integrity (Osmani and Labouesse, 2014;Toivola et al, 2015). This is well reflected in our study by the rapid loss of filamental structures containing keratin filaments.…”

Section: Mechanisms Of P38mapk and Lipid-raft-dependent Modulation Ofsupporting

confidence: 52%

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Vielmuth

Waschke

Spindler

2015

Journal of Investigative Dermatology

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Pemphigus vulgaris (PV) is a severe autoimmune disease in which autoantibodies against the desmosomal cell adhesion molecules desmoglein (Dsg) 1 and Dsg3 cause intraepidermal blister formation. Mechanistically, the fundamental question is still unresolved whether loss of cell cohesion is a result of (1) direct inhibition of Dsg interaction by autoantibodies or (2) intracellular signaling events, which are altered in response to antibody binding and finally cause desmosome destabilization. We used atomic force microscopy (AFM) to perform Dsg3 adhesion measurements on living keratinocytes to investigate the contributions of direct inhibition and signaling to loss of cell cohesion after autoantibody treatment. Dsg3 binding was rapidly blocked following antibody exposure under conditions where no depletion of surface Dsg3 was detectable, demonstrating direct inhibition of Dsg3 interaction. Inhibition of p38MAPK, a central signaling molecule in PV pathogenesis, abrogated loss of cell cohesion, but had a minor effect on loss of Dsg3 binding. Similarly, the cholesterol-depleting agent methyl-β-cyclodextrin (β-MCD) fully blocked cell dissociation, but did not restore Dsg3 interactions or prevent the activation of p38MAPK. These results demonstrate that inhibition of Dsg3 binding is not sufficient to cause loss of cell cohesion, but rather alters signaling events which, in lipid raft-dependent manner, induce cell dissociation.

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Section: Mechanisms Of P38mapk and Lipid-raft-dependent Modulation Ofsupporting

confidence: 52%

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Vielmuth

Waschke

Spindler

2015

Journal of Investigative Dermatology

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“…Possibly, plectin acts as a mechanosensor as it contains a cryptic SH3 domain in the fifth spectrin repeat of its plakin domain. Following mechanical stress, unfolding of spectrin domains may uncover the hidden SH3 domain (Osmani and Labouesse 2015).…”

Section: Intrinsic Keratin Properties and Associated Proteins As Detementioning

confidence: 99%

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

Hatzfeld

Keil

Magin

2017

Cold Spring Harb Perspect Biol

116

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Adherens junctions (AJs) and desmosomes connect the actin and keratin filament networks of adjacent cells into a mechanical unit. Whereas AJs function in mechanosensing and in transducing mechanical forces between the plasma membrane and the actomyosin cytoskeleton, desmosomes and intermediate filaments (IFs) provide mechanical stability required to maintain tissue architecture and integrity when the tissues are exposed to mechanical stress. Desmosomes are essential for stable intercellular cohesion, whereas keratins determine cell mechanics but are not involved in generating tension. Here, we summarize the current knowledge of the role of IFs and desmosomes in tissue mechanics and discuss whether the desmosome-keratin scaffold might be actively involved in mechanosensing and in the conversion of chemical signals into mechanical strength.

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“…Plectin and other plakins are essential to maintain the integrity of tissues that suffer high mechanical stress. Junctional complexes that contain plakins have also been implicated in sensing biomechanical changes in the surrounding extracellular environment (38). Yet, it is unclear how the plakin domain might contribute to these functions.…”

Section: Implications For the Role Of The Plakin Domain In The Mechanmentioning

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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Remodeling of keratin-coupled cell adhesion complexes

Cited by 35 publications

References 93 publications

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

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

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