Architecture and dynamics of a desmosome–endoplasmic reticulum complex

Bharathan, Navaneetha Krishnan; Giang, W.; Hoffman, C E; Aaron, Jesse; Khuon, Satya; Chew, Teng‐Leong; Preibisch, Stephan; Trautman, Eric T.; Heinrich, Larissa; Bogovic, John A.; Bennett, Davis; Ackerman, David G.; Park, Woo-Hyun; Petruncio, Alyson; Weigel, Aubrey V.; Saalfeld, Stephan; Vogl, A. Wayne; Stahley, Sara N.; Kowalczyk, Andrew P.

doi:10.1038/s41556-023-01154-4

Cited by 18 publications

(5 citation statements)

References 63 publications

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“…To experimentally determine whether palmitoylation drives DSG1 raft association, we stably expressed DSG1 PALM -GFP in DSG-null A431 cells. A431 cells are an immortal human carcinoma cell line commonly used to assess desmosome assembly and function (Godsel et al, 2005; Brennan et al, 2012; Baddam et al, 2018; Bharathan et al, 2023). DSG2 is the prevalent DSG isoform expressed in A431 cells (Schäfer et al, 1994, Zimmer et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

The transmembrane domain of the desmosomal cadherin desmoglein-1 governs lipid raft association to promote desmosome adhesive strength

Zimmer,

Giang,

Levental

et al. 2024

Preprint

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Cholesterol- and sphingolipid-enriched domains called lipid rafts are hypothesized to selectively coordinate protein complex assembly within the plasma membrane to regulate cellular functions. Desmosomes are mechanically resilient adhesive junctions that associate with lipid raft membrane domains, yet the mechanisms directing raft association of the desmosomal proteins, particularly the transmembrane desmosomal cadherins, are poorly understood. We identified the desmoglein-1 (DSG1) transmembrane domain (TMD) as a key determinant of desmoglein lipid raft association and designed a panel of DSG1TMD variants to assess the contribution of TMD physicochemical properties (length, bulkiness, and palmitoylation) to DSG1 lipid raft association. Sucrose gradient fractionations revealed that TMD length and bulkiness, but not palmitoylation, govern DSG1 lipid raft association. Further, DSG1 raft association determines plakoglobin recruitment to raft domains. Super-resolution imaging and functional assays uncovered a strong relationship between the efficiency of DSG1TMD lipid raft association and the formation of morphologically and functionally robust desmosomes. Lipid raft association regulated both desmosome assembly dynamics and DSG1 cell surface stability, indicating that DSG1 lipid raft association is required for both desmosome formation and maintenance. These studies identify the biophysical properties of desmoglein transmembrane domains as key determinants of lipid raft association and desmosome adhesive function.

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Section: Resultsmentioning

confidence: 99%

The transmembrane domain of the desmosomal cadherin desmoglein-1 governs lipid raft association to promote desmosome adhesive strength

Zimmer,

Giang,

Levental

et al. 2024

Preprint

Self Cite

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“…Several intracellular signals (e.g., p38MAPK signaling) that could lead to keratinocyte apoptosis have been investigated after binding of human pemphigus autoantibodies to desmosomal targets. A recent study revealed that tubules of endoplasmic reticulum (ER) are associated with desmosomes, and ER stress, a known activator of p38 MAPK pathway [ 33 ], develops with any type of desmosome or keratin filament perturbation [ 34 ]. Our canine PF lesional skin data showed upregulation of several p38 MAPK pathway genes, such as MAPK14, MAP2K4, MAPKAPK2, STAT4, IL-1R1, and tumor necrosis factor receptor-associated factor 6 (TRAF6).…”

Section: Discussionmentioning

confidence: 99%

Microarray Gene Expression Analysis of Lesional Skin in Canine Pemphigus Foliaceus

Starr,

Howerth,

Leon

et al. 2024

Veterinary Sciences

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Canine pemphigus foliaceus (PF) is considered the most common autoimmune skin disease in dogs; the mechanism of PF disease development is currently poorly understood. Therefore, this study aimed to characterize the molecular mechanisms and altered biological pathways in the skin lesions of canine PF patients. Using an RNA microarray on formalin-fixed, paraffin-embedded samples, we analyzed the transcriptome of canine PF lesional skin (n = 7) compared to healthy skin (n = 5). Of the 800 genes analyzed, 420 differentially expressed genes (DEGs) (p < 0.05) were found. Of those, 338 genes were significantly upregulated, including pro-inflammatory and Th17-related genes. Cell type profiling found enhancement of several cell types, such as neutrophils, T-cells, and macrophages, in PF skin compared to healthy skin. Enrichment analyses of the upregulated DEGs resulted in 78 statistically significant process networks (FDR < 0.05), including the Janus kinase signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein kinase (MAPK) signaling. In conclusion, canine PF lesional immune signature resembles previously published changes in human pemphigus skin lesions. Further studies with canine PF lesional skin using next-generation sequencing (e.g., RNA sequencing, spatial transcriptomics, etc.) and the development of canine keratinocyte/skin explant PF models are needed to elucidate the pathogenesis of this debilitating disease.

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“…3B ) and contact sites between the ER and endosomes, lysosomes, peroxisomes, and mitochondria (Phillips and Voeltz, 2016 ; Raiborg et al, 2015 ). In epithelial sheets, cell-cell junctions provide another way to tether organelles, as revealed by the association of the ER to desmosomes, a specialised and adhesive intercellular junction structure (Bharathan et al, 2023 ). Notably, also the existence of contact sites between membrane-less ribonucleoprotein (RNP) granules and the membrane-surrounded ER has been recently revealed, which regulate the fission of the membrane-less granules (Lee et al, 2020 ).…”

Section: Forces and Anchors For Organelle Positioningmentioning

confidence: 99%

Principles of organelle positioning in motile and non-motile cells

Kroll,

Renkawitz

2024

EMBO Rep

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Cells are equipped with asymmetrically localised and functionally specialised components, including cytoskeletal structures and organelles. Positioning these components to specific intracellular locations in an asymmetric manner is critical for their functionality and affects processes like immune responses, tissue maintenance, muscle functionality, and neurobiology. Here, we provide an overview of strategies to actively move, position, and anchor organelles to specific locations. By conceptualizing the cytoskeletal forces and the organelle-to-cytoskeleton connectivity, we present a framework of active positioning of both membrane-enclosed and membrane-less organelles. Using this framework, we discuss how different principles of force generation and organelle anchorage are utilised by different cells, such as mesenchymal and amoeboid cells, and how the microenvironment influences the plasticity of organelle positioning. Given that motile cells face the challenge of coordinating the positioning of their content with cellular motion, we particularly focus on principles of organelle positioning during migration. In this context, we discuss novel findings on organelle positioning by anchorage-independent mechanisms and their advantages and disadvantages in motile as well as stationary cells.

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Architecture and dynamics of a desmosome–endoplasmic reticulum complex

Cited by 18 publications

References 63 publications

The transmembrane domain of the desmosomal cadherin desmoglein-1 governs lipid raft association to promote desmosome adhesive strength

The transmembrane domain of the desmosomal cadherin desmoglein-1 governs lipid raft association to promote desmosome adhesive strength

Microarray Gene Expression Analysis of Lesional Skin in Canine Pemphigus Foliaceus

Principles of organelle positioning in motile and non-motile cells

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