Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

Abstract

The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. There is still no cure to the disease apart from the use of corticosteroids and immunosuppressive agents. Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. Thus, further understanding of the molecular basis underlying this disease process is vital to develop targeted therapies. Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. DSG3 is a pivotal player in mediating outside-in signaling involved in cell junction remodeling, cell proliferation, differentiation, migration or apoptosis, thus validating its biological function in tissue integrity and homeostasis beyond desmosome adhesion. Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. The purpose of this review is to summarize the earlier and recent advances highlighting our recent findings related to PV pathogenesis that may pave the way for future research to develop novel specific therapies in curing this disease.

Desmoglein‐3 induces YAP phosphorylation and inactivation during collective migration of oral carcinoma cells

“…A previous study failed to detect hyperplastic changes in mice with Mst1/2 depletion nor in human HaCaT keratinocytes with LATS1/2 knockdown [ 49 ]. Since DSG3 is identified as a versatile signalling molecule and can influence various signalling pathways [ 15 , 19 , 20 , 21 , 22 , 23 , 24 , 38 , 59 , 71 ], it may function as a potential key component in Hippo signalling. Further study is needed in deciphering its role in the Hippo pathway.…”

Recent advances in the role of Yes‐associated protein in dermatosis

“…YAP is overexpressed around pemphigus lesions. 39 and adherens junctions. 39,40 Dsg3 was shown to form a complex with phosphorylated YAP under high mechanical tension, contradicting a previous report that phosphorylated YAP is inactive.…”

“…39 and adherens junctions. 39,40 Dsg3 was shown to form a complex with phosphorylated YAP under high mechanical tension, contradicting a previous report that phosphorylated YAP is inactive. 41 However, the function of phosphorylated YAP in keratinocytes remains to be determined.…”

“…YAP is overexpressed around pemphigus lesions 39 . Desmoglein 3 (Dsg3) and immunoglobulin G (IgG) are essential for the induction and progression of bullous skin disease; Dsg3 is destroyed by IgG to generate reactive oxygen species (ROS), which acts directly on various signaling pathways including α‐catenin, Dsg3, p38 mitogen‐activated protein kinase (MAPK), c‐Jun N‐terminal kinase, and protein kinase C to upregulate YAP.…”

Desquamative Gingivitis in the Context of Autoimmune Bullous Dermatoses and Lichen Planus—Challenges in the Diagnosis and Treatment

“…In the mucosa, DSG3 is expressed throughout the epithelium, while DSG1 is predominantly expressed in the superficial layers, and therefore the loss of DSG3 cannot be adequately compensated by DSG1. Exclusive reactivity to DSG3 causes only mucosal lesions [ 44 , 45 ].…”