Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin.
The autoimmune disease pemphigus vulgaris (PV) manifests as loss of keratinocyte cohesion triggered by autoantibody binding to desmoglein (Dsg)3, an intercellular adhesion molecule of mucous membranes, epidermis, and epidermal stem cells. Here we describe a so far unknown signaling cascade activated by PV antibodies. It extends from a transient enhanced turn over of cell surface-exposed, nonkeratin-anchored Dsg3 and associated plakoglobin (PG), through to depletion of nuclear PG, and as one of the consequences, abrogation of PG-mediated c-Myc suppression. In PV patients (6/6), this results in pathogenic c-Myc overexpression in all targeted tissues, including the stem cell compartments. In summary, these results show that PV antibodies act via PG to abolish the c-Myc suppression required for both maintenance of epidermal stem cells in their niche and controlled differentiation along the epidermal lineage. Besides a completely novel insight into PV pathogenesis, these data identify PG as a potent modulator of epithelial homeostasis via its role as a key suppressor of c-Myc.
Williamson
Lina
L
Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Raess
Natalia A
NA
Caldelari
Reto
R
Zakher
Anthony
A
de Bruin
Alain
A
Posthaus
Horst
H
Bolli
Reinhard
R
Hunziker
Thomas
T
Suter
Maja M
MM
Müller
Eliane J
EJ
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010392:Pemphigus / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000378:metabolism*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics; D051185:gamma Catenin / Q000235:genetics / Q000502:physiology*
C495293:Jup protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D051176:beta Catenin; D051185:gamma Catenin