Desmoglein Endocytosis and Desmosome Disassembly Are Coordinated Responses to Pemphigus Autoantibodies*

  title={Desmoglein Endocytosis and Desmosome Disassembly Are Coordinated Responses to Pemphigus Autoantibodies*},
  author={Cathárine C. Calkins and Shannon V Setzer and Jean Marie Jennings and Susan Summers and Kazuyuki Tsunoda and Masayuki Amagai and Andrew P. Kowalczyk},
  journal={Journal of Biological Chemistry},
  pages={7623 - 7634}
Desmosomes are adhesive intercellular junctions prominent in the skin and heart. Loss of desmosome function is associated with severe congenital and acquired disorders characterized by tissue fragility. Pemphigus vulgaris (PV) is an autoimmune disorder in which antibodies are directed against the desmosomal adhesion molecule Dsg3, resulting in severe mucosal erosions and epidermal blistering. To define the mechanisms by which Dsg3 autoantibodies disrupt keratinocyte adhesion, the fate of PV IgG… 

Disruption of desmosome assembly by monovalent human pemphigus vulgaris monoclonal antibodies.

Immunofluorescence and ELISA studies indicate that pathogenic PV mAbs specifically cause internalization of newly synthesized Dsg3 during desmosome assembly, correlating with their pathogenic activity.

Keratin Retraction and Desmoglein3 Internalization Independently Contribute to Autoantibody-Induced Cell Dissociation in Pemphigus Vulgaris

Pemphigus vulgaris (PV) is a potentially lethal autoimmune disease characterized by blister formation of the skin and mucous membranes and is caused by autoantibodies against desmoglein (Dsg) 1 and

Desmosome disassembly in response to pemphigus vulgaris IgG occurs in distinct phases and can be reversed by expression of exogenous Dsg3.

Analysis of primary human keratinocytes and patient IgG support a model in which PV IgG cause the loss of cell adhesion by altering the dynamics of Dsg3 assembly into desmosomes and the turnover of cell surface pools of DSG3 through endocytic pathways.

p38MAPK Signaling and Desmoglein-3 Internalization Are Linked Events in Pemphigus Acantholysis*

The data suggest that p38MAPK is capable of regulating PV IgG-mediated DSG3 internalization and that previously isolated mechanistic observations may be linked to a common pathway by which pemphigus autoantibodies lead to acantholysis.

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

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.

Keratins Regulate p38MAPK-Dependent Desmoglein Binding Properties in Pemphigus

It is concluded that p38MAPK signaling is (i) critical for regulation of cell adhesion, (ii) regulated by keratins, and (iii) targets both keratin-dependent and -independent mechanisms.

Plakophilin-1 protects keratinocytes from pemphigus vulgaris IgG by forming calcium-independent desmosomes

It is reported that enhanced expression of PKP-1 protects keratinocytes from PV IgG-induced loss of cell-cell adhesion and transforms desmosome adhesion from a calcium-dependent to acium-independent and hyper-adhesive state.

Super-resolution microscopy reveals altered desmosomal protein organization in pemphigus vulgaris patient tissue

Findings indicate that Dsg3 clustering and endocytosis are associated with reduced desmosome size and adhesion defects in PV patient tissue, and reveals that super-resolution optical imaging is powerful approach for studying epidermal adhesion structures in normal and diseased skin.

150th Anniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

Pemphigus could be referred to a “desmosome-remodeling disease involving pemPHigus IgG-activated outside-in signaling events”, which may explain different clinical (non-inflammatory, inflammatory, and necrolytic) types of pemphIGus.

Internalization of Non-Clustered Desmoglein 1 without Depletion of Desmoglein 1 from Adhesion Complexes in An Experimental Model of the Autoimmune Disease Pemphigus Foliaceus

Investigation of changes in subcellular distribution of Dsg1 in response to serum of patients with PF by using an in vitro model of PF suggests that anti-Dsg1 antibodies from PF serum could cause the internalization of non-clustered Dsg 1 and perturb the formation of new desmosomes but not directly disrupt Dsg2-containing junctions when stable contacts are already formed.



IgG binds to desmoglein 3 in desmosomes and causes a desmosomal split without keratin retraction in a pemphigus mouse model.

Findings indicate that anti-Dsg3 IgG antibodies can directly access Dsg3 present in desmosomes in vivo and cause the subsequent desmosome separation that leads to blister formation in PV.

Pemphigus foliaceus IgG causes dissociation of desmoglein 1-containing junctions without blocking desmoglein 1 transinteraction.

It is shown in an in vitro system that IgGs purified from PF patient sera caused cellular dissociation of cultured human keratinocytes as well as significant release of Dsg1-coated microbeads attached to Dsg-containing sites on the keratinocyte cellular surface.

A Central Role for the Armadillo Protein Plakoglobin in the Autoimmune Disease Pemphigus Vulgaris

The establishment of an in vitro model allowed us to exclude the steric hindrance only hypothesis, and to demonstrate for the first time that plakoglobin plays a central role in PV, a finding that will provide a novel direction for investigations of the molecular mechanisms leading to PV, and on the function ofplakoglobin in differentiating keratinocytes.

Internalization of constitutive desmogleins with the subsequent induction of desmoglein 2 in pemphigus lesions

Findings indicate an alteration of Dsg isoform expression in subclinical pemphigus lesions, which might be related to the characteristic acantholytic patterns: the suprabasilar layer in PV and the upper epidermis in PF.

Assembly Pathway of Desmoglein 3 to Desmosomes and Its Perturbation by Pemphigus Vulgaris-IgG in Cultured Keratinocytes, as Revealed by Time-Lapsed Labeling Immunoelectron Microscopy

Dsg3 first forms simple clusters, followed by KIF-attachment, and then becomes integrated into desmosomes, and that PV-IgG-induced internalization of the nondesmosomal simple clusters of Dsg3 may represent the primary effects of PV- IgG on keratinocytes.

Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris

It is suggested that pemphigus autoantibodies might interfere directly with such a function of DSG3, and the critical importance of Dsg3 for adhesion in deep stratified squamous epithelia is demonstrated.

Desmosomes and disease: pemphigus and bullous impetigo.

Pemphigus vulgaris-IgG causes a rapid depletion of desmoglein 3 (Dsg3) from the Triton X-100 soluble pools, leading to the formation of Dsg3-depleted desmosomes in a human squamous carcinoma cell line, DJM-1 cells.

A novel interpretation for a better understanding of mechanisms for blistering in PV is provided, a possibility that PV-IgG generates the formation of aberrant desmosomes, which are lacking in Dsg3, but not other desmosomal constituents.

Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent.

Findings indicate that formation of the conformational epitopes on the pemphigus antigens is dependent on calcium but independent of glycosylation, and provide direct evidence that calcium plays an important role in determining the antigenic properties of the p emphigu antigen.