Serum and IgG isolated from patients with the autoimmune blistering disease Pemphigus Vulgaris (PV) trigger complex intracellular pathways in keratinocytes, including alterations of the cell cycle and metabolism, which ultimately lead to cell-cell detachment (acantholysis). We have shown previously that one of the earliest pathogenic events in PV is the activation of protein kinases. In the present study, we show that the PKR-like endoplasmic reticulum (ER) kinase PERK is activated in keratinocytes exposed to PV serum, as demonstrated by an increase in p-PERK levels and phosphorylation of eIF2alpha. Decreased expression of PERK by siRNA reduced the effects of PV serum on the cell cycle and keratinocyte viability, two key events in PV pathophysiology. Since impairment of metabolic activity in PV is partially due to non-IgG serum factors, we investigated the activation of PERK in keratinocytes incubated with whole PV serum, purified PV IgG and IgG-depleted PV serum using real time in-cell ELISA. The data demonstrated that PV sera depleted of IgG, but not PV IgG, triggered PERK phosphorylation and this correlated with a marked reduction of metabolic activity in keratinocytes exposed to IgG-free serum. Knockdown of PERK by siRNA abrogated the changes in the cell cycle and apoptosis induced by IgG-depleted PV serum. Finally, the reduction of metabolic activity observed in keratinocytes exposed to IgG-depleted PV serum was absent in PERK-deficient cells. Taken together, the results demonstrate that activation of PERK participates in the reduction of metabolic activity and cell viability seen in PV and that this phenomenon depends on non-IgG factors. PERK activation may represent a novel signalling mechanism linking ER stress and acantholysis in PV.
|Translated title of the contribution||Deregulation of PERK in the autoimmune disease Pemphigus Vulgaris occurs via IgG-independent mechanisms|
|Pages (from-to)||in press|
|Number of pages||8|
|Journal||British Journal of Dermatology|
|Publication status||Published - 2010|
Bibliographical noteAuthor of Publication Reviewed: Lanza A, Lanza M, Santoro R, Soro V, Prime SS, Cirillo N
Other: IF = 4.260