The keratin–desmosome scaffold: pivotal role of desmosomes for keratin network morphogenesis

Moch, Marcin; Schwarz, Nicole; Windoffer, Reinhard; Leube, Rudolf E.

doi:10.1007/s00018-019-03198-y

Cited by 41 publications

(55 citation statements)

References 61 publications

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“…Until recently, there was no data that desmosomes actively control IF assembly or organization beyond simply binding pre-existing filaments. However, Leube and colleagues recently imaged events that appear to be the de novo nucleation of keratin filaments at desmosomes (Moch et al, 2020). This finding extended prior work demonstrating that keratin filaments were nucleated near focal complexes at the leading edge of migrating cells (Windoffer et al, 2006).…”

Section: Introductionmentioning

confidence: 57%

“…We next asked whether Ndel1 promotes keratin organization at desmosomes, as Ndel1 localizes to these structures and they are important sites for keratin organization and assembly in keratinocytes (Moch et al, 2020;Sumigray et al, 2011). We therefore transfected cells with GFP-tagged keratin 14 (K14-GFP) to visualize keratin organization.…”

Section: Ndel1 Affects Keratin Organization In Keratinocytesmentioning

confidence: 99%

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Ndel1 promotes keratin assembly and desmosome stability

Kim

Hlavaty

Maycock

et al. 2020

Preprint

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Keratin intermediate filaments form dynamic polymer networks that organize in specific ways dependent on the cell type, the stage of the cell cycle, and the state of the cell. In differentiated cells of the epidermis, they are organized by desmosomes, cell-cell adhesion complexes which provide essential mechanical integrity to this tissue. Despite this, we know little about how keratin organization is controlled and whether desmosomes actively promote keratin assembly in addition to binding pre-assembled filaments. We recently discovered that Ndel1 is a desmosome-associated protein in differentiated epidermis. Here, we show that Ndel1 binds directly to keratin subunits through a motif conserved in all intermediate filament proteins.Further, Ndel1 is necessary for robust desmosome-keratin association and sufficient to reorganize keratins to distinct cellular sites. Lis1, a Ndel1 binding protein, is required for desmosomal localization of Ndel1, but not for its effects on keratin filaments. Finally, we use mouse genetics to demonstrate that loss of Ndel1 results in desmosome defects in the epidermis. Our data thus identify Ndel1 as a desmosome-associated protein which promotes local assembly/organization of keratin filaments and is essential for both robust cell adhesion and epidermal barrier function.

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Section: Introductionmentioning

confidence: 57%

Section: Ndel1 Affects Keratin Organization In Keratinocytesmentioning

confidence: 99%

Ndel1 promotes keratin assembly and desmosome stability

Kim

Hlavaty

Maycock

et al. 2020

Preprint

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“…Our immunoprecipitation data demonstrate that E-Cad interacts with Dsg3 and Dsc3 to similar extents in ctrl and ko cell lines, indicative of regular initial steps of desmosome formation. Live cell imaging studies suggest that Dp from cytosolic pools subsequently locates to nascent desmosomal cadherin clusters (Godsel et al, 2005, Moch et al, 2020. In view of the observation that the Dp ko cells generated in this study do not exhibit ultrastructurally detectable desmosomes but rather show desmosomal cadherins scattered in small clusters in the membrane, it appears that Dp is required to coalesce and stabilize these small clusters into larger assemblies, finally yielding mature desmosomes.…”

Section: Dp Does Not Regulate Interaction Properties But Is Required mentioning

confidence: 73%

“…This demonstrates that extradesmosomal cadherins do not significantly contribute to cell cohesion and fusion of small clusters into desmosomes is required in this regard. As desmosomes were shown to organize the keratin network adjacent to the plasma membrane (Moch et al, 2020), it is possible that Dp is an important organizing center for both desmosomal cadherins and keratins.…”

Section: Dp Does Not Regulate Interaction Properties But Is Required mentioning

confidence: 99%

Clustering of desmosomal cadherins by desmoplakin is essential for cell-cell adhesion

Wanuske

Brantschen

Schinner

et al. 2020

Preprint

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ABBREVIATIONS AFM = atomic force microscopy; ctrl = control; CTV = CellTrace Violet; Dp = desmoplakin; Dsc = desmocollin; Dsg = desmoglein; E-Cad = E-cadherin; FRAP = fluorescence recovery after photo bleaching; ko = knockout; Pg = plakoglobin; Pkp = plakophilin; SIM = structured illumination microscopy; wt = wildtype; β-Cat = β-catenin; 3 ABSTRACT Desmoplakin (Dp) localizes to desmosomes, linking clusters of desmosomal adhesion molecules to the intermediate filament cytoskeleton. Here, we generated Dp knockout (ko) cell lines of human keratinocytes to study the impact on desmosomal adhesion molecules and desmosome turnover using atomic force microscopy and superresolution imaging. In comparison to ko of another desmosomal component, plakoglobin (Pg), loss of Dp resulted in absence of desmosomes and drastically impaired cell cohesion. In Dp ko, the desmosomal adhesion molecules desmoglein 2 (Dsg2) and desmocollin 3 (Dsc3) were redistributed into small clusters in the cell membrane with no further increase in loss of intercellular adhesion by silencing of Dsg2. This suggests that extradesmosomal cadherins do not significantly contribute to cell cohesion but rather localization within desmosomes is required. Our data outline a crucial role of Dp for both desmosomal molecule clustering and mature desmosome formation and provide novel insights into the regulation of intercellular adhesion.

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“…Our observation by TEM of reduced desmosome numbers in α-adducin-deficient cells supports this hypothesis. Nascent desmosomes serve as nucleation sites for keratin filaments (Godsel et al, 2005, Moch et al, 2019. Vice versa, the binding properties of desmosomal cadherins are compromised if keratins are absent, indicating an inside-out regulation of desmosomal adhesion on the single molecule level by intermediate filaments (Vielmuth et al, 2018b).…”

Section: Impact Of α-Adducin On Desmosome Formationmentioning

confidence: 99%

The actin binding protein α-adducin modulates desmosomal turnover and plasticity

Hiermaier

Kliewe

Schinner

et al. 2019

Preprint

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Short Title: α-adducin modulates desmosomal turnover 2 ABBREVIATIONS: Add1 = α-adducin; AFM = atomic force microscope; BSA = bovine serum albumin; ctrl = control; Dsg = desmoglein; E-Cad = cadherin; FDC = force-distance curve; FRAP = fluorescent recovery after photobleaching; ko = knockout; MEK = murine keratinocyte; scFv = single chain variable fragment; wt = wildtype; ORCIDs:ABSTRACT Intercellular adhesion is essential for tissue integrity and homeostasis. Desmosomes are especially abundant in the epidermis and the myocardium, tissues, which are under constantly changing mechanical stresses. Yet, it is largely unclear whether desmosomal adhesion can be rapidly adapted to changing demands and the mechanisms underlying desmosome turnover are only partially understood. We here show that loss of the actin-binding protein α-adducin prevented the ability of cultured keratinocytes or murine epidermis to withstand mechanical stress paralleled with reduced desmosome number. This effect was not caused by decreased levels or impaired adhesive properties of desmosomal molecules but rather by altered desmosome turnover. Mechanistically, reduced cortical actin density in α-adducin knockout keratinocytes resulted in increased mobility of the desmosomal adhesion molecule desmoglein 3 (Dsg3) and impaired interactions with Ecadherin, a crucial step in desmosome formation. Accordingly, loss of α-adducin prevented increased membrane localization of Dsg3 in response to cyclic stretch or shear stress. Our data demonstrate plasticity of desmosomal molecules in response to mechanical stimuli and unravel a mechanism how the actin cytoskeleton indirectly shapes intercellular adhesion by restricting the mobility of desmosomal molecules.

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The keratin–desmosome scaffold: pivotal role of desmosomes for keratin network morphogenesis

Cited by 41 publications

References 61 publications

Ndel1 promotes keratin assembly and desmosome stability

Ndel1 promotes keratin assembly and desmosome stability

Clustering of desmosomal cadherins by desmoplakin is essential for cell-cell adhesion

The actin binding protein α-adducin modulates desmosomal turnover and plasticity

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