Dsg2 Upregulation as a Rescue Mechanism in Pemphigus

Abstract

In the bullous autoimmune disease pemphigus, autoantibodies directed against the desmosomal cadherins desmoglein (Dsg)1 and 3 cause loss of intercellular adhesion clinically manifested as flaccid blisters of the skin and mucous membranes. We showed that homophilic Dsg3 interactions are directly inhibited upon autoantibody binding and recently observed that Dsg3 also undergoes heterophilic interactions with Dsg2. Thus, we here investigated the impact of this heterophilic interaction in pemphigus. Dsg2, which is almost absent in healthy, adult epidermis, was upregulated in epidermis of pemphigus patients. Similarly, pemphigus autoantibodies induced upregulation of Dsg2 in a human ex‐vivo skin model. Further, a newly generated stable murine Dsg3‐deficient keratinocyte cell line showed severely disturbed intercellular adhesion in keratinocytes dissociation assay paralleled by upregulation of Dsg2 in the cytoskeletal‐bound membrane fraction. Heterophilic interactions were confirmed by Dsg2‐Dsg3 co‐immunoprecipitation in human keratinocytes. We next characterized heterophilic Dsg2‐Dsg3 interactions by cell‐free atomic force microscopy, which showed binding frequency, ‐strength, Ca2+‐dependency and a catch‐bond behavior comparable to the homophilic Dsg3 interaction. A pathogenic pemphigus aDsg3 antibody from a pemphigus model, AK23, and autoantibodies from a pemphigus patient directly interfere with homophilic Dsg3 binding. Interestingly, direct inhibition was significantly less pronounced for heterophilic Dsg3‐Dsg2 interactions. In contrast, an aDsg2 blocking antibody reduced heterophilic Dsg3‐Dsg2 and homophilic Dsg2‐Dsg2 binding to the same degree. Consequently, the aDsg2 antibody severely impaired already disturbed intercellular cohesion of Dsg3‐deficient keratinocytes, underlining the importance of Dsg2 for intercellular adhesion if Dsg3 is missing. Moreover, heterophilic Dsg2‐Dsg3 interactions showed a longer life‐time compared to homophilic Dsg2‐Dsg2 interactions which may contribute to their biological importance when Dsg3 homophilic interactions are compromised. Taken together, the data show that Dsg2 undergoes heterophilic interactions with Dsg3, which may serve as a compensatory mechanism to attenuate autoantibody‐induced loss of keratinocyte adhesion in pemphigus. This further reflects the biological significance of heterophilic Dsg3 interactions under pathological conditions.Support or Funding InformationDFG FOR 2497 to JW, Else‐Kröner‐Fresenius‐Stiftung 2016_AW157 to FV