Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization.
In the human autoimmune blistering disease pemphigus vulgaris (PV) pathogenic antibodies bind the desmosomal cadherin desmoglein-3 (dsg3), causing epidermal cell-cell detachment (acantholysis). Pathogenic PV dsg3 autoantibodies were used to initiate desmosome signaling in human keratinocyte cell cultures. Heat shock protein 27 (HSP27) and p38MAPK were identified as proteins rapidly phosphorylated in response to PV IgG. Inhibition of p38MAPK activity prevented PV IgG-induced HSP27 phosphorylation, keratin filament retraction, and actin reorganization. These observations suggest that PV IgG binding to dsg3 activates desmosomal signal transduction cascades leading to (i) p38MAPK and HSP27 phosphorylation and (ii) cytoskeletal reorganization, supporting a mechanistic role for signaling in PV IgG-induced acantholysis. Targeting desmosome signaling via inhibition of p38MAPK and HSP27 phosphorylation may provide novel treatments for PV and other desmosome-associated blistering diseases.
Berkowitz
Paula
P
Department of Dermatology, University of North Carolina-Chapel Hill School of Medicine, 27599, USA.
Hu
Peiqi
P
Liu
Zhi
Z
Diaz
Luis A
LA
Enghild
Jan J
JJ
Chua
Michael P
MP
Rubenstein
David S
DS
D000199:Actins / Q000378:metabolism; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000648:ultrastructure*; D003896:Desmosomes / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology*; D007633:Keratins / Q000378:metabolism; D010392:Pemphigus / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000199:Actins; D006360:Heat-Shock Proteins; D007074:Immunoglobulin G; D007633:Keratins; D048051:p38 Mitogen-Activated Protein Kinases