Abstract
Poly(ADP-ribose) polymerase 1 (PARP-1) is an ADP-ribosylating enzyme participating in diverse cellular functions. The roles of PARP-1 in the immune system, however, have not been well understood. Here we find that PARP-1 interacts with FOXP3 and induces its poly(ADP-ribosyl)ation. By using PARP-1 inhibitors, we show that reduced poly(ADP-ribosyl)ation of FOXP3 results in not only FOXP3 stabilization and increased FOXP3 downstream genes but also enhanced suppressive function of regulatory T cells. Our results suggest that PARP-1 negatively regulates the suppressive function of Treg cells at the posttranslational level via FOXP3 poly(ADP-ribosyl)ation. This finding has implications for developing PARP-1 inhibitors as potential agents for the prevention and treatment of autoimmune diseases.
Highlights
Poly(ADP-ribose) polymerase 1 (PARP-1) has importance in the immune system
In a co-immunoprecipitation assay in which Myc-tagged Poly(ADP-ribose) polymerases (PARP)-1 and FLAG-tagged Forkhead box P3 (FOXP3) were co-transfected into HEK293T cells, we found that PARP-1 interacted with FOXP3 in reciprocal immunoprecipitation (Fig. 1A)
Treated Treg cells exhibited a much stronger suppressive effect than untreated Treg cells on the proliferation of peripheral blood mononuclear cell (PBMC) (Fig. 6B), suggesting that the poly(ADP-ribosyl)ation of FOXP3 mediated by PARP-1 negatively regulates the suppressive function of Treg cells
Summary
Results: Poly(ADP-ribosyl)ation of FOXP3 mediated by PARP-1 destabilizes FOXP3 and negatively regulates the suppressive activity of Treg cells. Our results suggest that PARP-1 negatively regulates the suppressive function of Treg cells at the posttranslational level via FOXP3 poly(ADP-ribosyl)ation This finding has implications for developing PARP-1 inhibitors as potential agents for the prevention and treatment of autoimmune diseases. We find that, after treatment with PARP-1specific inhibitors, decreased poly(ADP-ribosyl)ation of FOXP3 in Treg cells leads to an increased level of FOXP3 by preventing proteasome-mediated degradation, resulting in an increased suppressive function of Treg cells. Our results suggest that PARP-1 negatively regulates the suppressive function of Treg cells at the posttranslational level through FOXP3 poly(ADP-ribosyl)ation
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