Desmoglein 1 Deficiency Causes Lethal Skin Blistering

Kugelmann, Daniela; Radeva, Mariya Y.; Spindler, Volker; Waschke, Jens

doi:10.1016/j.jid.2019.01.002

Cited by 29 publications

(24 citation statements)

References 19 publications

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“…Interfering with the superficial DSM cadherin Dsg1 has a similar impact on TJs: in both cases, the TJ protein ZO-1 accumulates aberrantly in the spinous layer, losing its restricted positioning in the SG2 layer (Broussard et al, unpublished data). The importance of Dsg1 for TJs was also observed in Dsg1 knockout animal models 117 (Godsel, Roth-Carter et al, unpublished data). Loss of PKP1, which associates with both DP and Dsg1, also results in impaired TJ function 118 .…”

Section: Desmosomes and Tight Junctionsmentioning

confidence: 69%

Desmosomes: Essential contributors to an integrated intercellular junction network

2019

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F1000 Faculty Reviews are written by members of the prestigious . They are F1000 Faculty commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. AbstractThe development of adhesive connections between cells was critical for the evolution of multicellularity and for organizing cells into complex organs with discrete compartments. Four types of intercellular junction are present in vertebrates: desmosomes, adherens junctions, tight junctions, and gap junctions. All are essential for the development of the embryonic layers and organs as well as adult tissue homeostasis. While each junction type is defined as a distinct entity, it is now clear that they cooperate physically and functionally to create a robust and functionally diverse system. During evolution, desmosomes first appeared in vertebrates as highly specialized regions at the plasma membrane that couple the intermediate filament cytoskeleton at points of strong cell-cell adhesion. Here, we review how desmosomes conferred new mechanical and signaling properties to vertebrate cells and tissues through their interactions with the existing junctional and cytoskeletal network.

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Section: Desmosomes and Tight Junctionsmentioning

confidence: 69%

Desmosomes: Essential contributors to an integrated intercellular junction network

2019

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“…Dsg1 appears to be more critical for epidermal integrity compared to Dsg3 because Dsg3-deficient mice develop mild skin lesions, which spontaneously heal, whereas Dsg1-deficient mice completely lose superficial epidermal layers during birth and die within 24 h (51, 52). However, Dsg3-specific antibodies were effective to cause skin blistering in mice (53) whereas in patients as well as in human epidermis ex vivo antibodies against Dsg3 alone usually are not sufficient to cause skin blisters (1, 37).…”

Section: Discussionmentioning

confidence: 99%

Role of Dsg1- and Dsg3-Mediated Signaling in Pemphigus Autoantibody-Induced Loss of Keratinocyte Cohesion

et al. 2019

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Pemphigus is an autoimmune dermatosis in which mucocutaneous blisters are induced primarily by autoantibodies against Desmoglein (Dsg) 1 and 3. Pemphigus vulgaris (PV) usually is associated with autoantibodies against Dsg3 whereas pemphigus foliaceus (PF) patients present autoantibodies against Dsg1. Several signaling pathways were proposed to cause loss of keratinocyte adhesion. However, relevance of different signaling pathways and role of Dsg1 and 3 to trigger signaling are not fully understood. Here, we show that Ca 2+ chelation reduced PV-IgG- and PF-IgG-mediated loss of HaCaT keratinocyte cohesion whereas EGFR inhibition did not inhibit effects of PF-IgG. PV-IgG activated EGFR in a Src-dependent manner whereas both PV-IgG and PF-IgG caused Ca 2+ influx independent of EGFR. ERK activation was Src-dependent in response to PV-IgG but not PF-IgG. To delineate the roles of Dsg isoforms to trigger signaling pathways, Dsg3- and Dsg2-deficient HaCaT keratinocyte cell lines were generated using CRISPR/Cas9. Dsg3- but not Dsg2-deficient cells were protected against PV-IgG-induced loss of cell adhesion. Ca 2+ influx and ERK activation in response to PF-IgG were preserved in both cell lines.

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“…Steric hindrance as a mechanism in pemphigus pathophysiology has been suggested by the following evidence: (i) Pathogenic pemphigus Abs recognized the EC1 region that is important for Dsg transinteraction (Ishii et al, 2008;Payne et al, 2005;Sekiguchi et al, 2001), and (ii) Dsg1 and Dsg3 knockout mice showed similar blisters as seen in pemphigus patients (Chen et al, 2008;Koch et al, 1997;Kugelmann et al, 2019). These data suggest that inactivation of Dsgs either by targeting the adhesion domain or genetically eliminating the molecule could result in typical pemphigus lesions.…”

Section: Discussionmentioning

confidence: 94%

Pemphigus Vulgaris and Foliaceus IgG Autoantibodies Directly Block Heterophilic Transinteraction between Desmoglein and Desmocollin

Ishii

Yoshida

Stanley

et al. 2020

Journal of Investigative Dermatology

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Desmoglein 1 Deficiency Causes Lethal Skin Blistering

Abstract: effects of caffeine on hair shaft elongation, matrix and outer root sheath keratinocyte proliferation, and transforming growth factor-b2/insulin-like growth factor-1-mediated regulation of the hair cycle in male and female human hair follicles in vitro. Br J Dermatol 2014;171: 1031e43.

Cited by 29 publications

References 19 publications

Desmosomes: Essential contributors to an integrated intercellular junction network

Desmosomes: Essential contributors to an integrated intercellular junction network

Role of Dsg1- and Dsg3-Mediated Signaling in Pemphigus Autoantibody-Induced Loss of Keratinocyte Cohesion

Pemphigus Vulgaris and Foliaceus IgG Autoantibodies Directly Block Heterophilic Transinteraction between Desmoglein and Desmocollin

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