p38MAPK signaling and desmoglein-3 internalization are linked events in pemphigus acantholysis.
Pemphigus vulgaris (PV) is an autoimmune blistering disease in which antibodies against the desmosomal cadherin, DSG3 (desmoglein-3), cause acantholysis. It has become increasingly clear that loss of cell-cell adhesion in PV is a complex and active process involving multiple signaling events such as activation of p38MAPK. It has also been demonstrated that incubating keratinocytes with PV IgG causes a redistribution of DSG3 from the cell surface to endosomes, which target these proteins for degradation. This study was undertaken to determine the relationship between p38MAPK and DSG3 endocytosis in pemphigus. In this work, we confirm that PV IgG causes internalization of cell-surface DSG3 into endosomes (as early as 4 h), which are then depleted from both detergent-soluble and detergent-insoluble pools. Cell-surface DSG3 internalization and depletion from both the detergent-soluble and detergent-insoluble fractions were blocked by the p38MAPK inhibitor SB202190. These 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.
Jolly
Puneet S
PS
Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina 27599-7287, USA.
Berkowitz
Paula
P
Bektas
Meryem
M
Lee
Hua-En
HE
Chua
Michael
M
Diaz
Luis A
LA
Rubenstein
David S
DS
D001323:Autoantibodies / Q000737:chemistry; D019921:Biotinylation; D002462:Cell Membrane / Q000378:metabolism; D051184:Desmoglein 3 / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D015603:Keratinocytes / Q000166:cytology; D018613:Microscopy, Confocal / Q000379:methods; D010392:Pemphigus / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D001323:Autoantibodies; D051184:Desmoglein 3; D003902:Detergents; D007074:Immunoglobulin G; D048051:p38 Mitogen-Activated Protein Kinases