Pin1 attenuates Fas-mediated apoptosis through binding to FADD in activated eosinophils. (57.1)

Abstract

Abstract Pin1 is widely expressed peptidyl-prolyl isomerase (PPIase) that plays a key role in a variety of events including cell cycle progression, response to viruses, expression of cytokines and cell death. Eosinophils (Eos) rely on Pin1 to mediate prosurvival signaling induced by IL-5 or GM-CSF by binding to and inhibiting pro-apoptotic Bax. Here we show Pin1 also participates in Fas-mediated apoptosis of Eos. Fas activation suppressed Pin1 activity despite co-treatment with IL-5. This was accompanied by phosphorylation of Pin1 at Ser16 and increased nuclear, rather than plasma membrane localization. Anti-Fas alone or in combination with IL-5 rapidly triggered FADD phosphorylation at Ser194. Interestingly, only the combination of agonists induced a stable interaction between P-FADD and Pin1. These results suggested Ser194-Pro195 was the Pin1 binding site in FADD. Consistent with this, phospho-mimic Ser194Glu FADD mutants preferentially interacted with Pin1 in vitro compared to WT or Ser194Ala mutants. Introduction of FADD Ser194Glu mutants significantly accelerated Eos apoptosis compared to WT or S194A. Therefore, our data suggest that Pin1 participates in extrinsic apoptosis via an interaction with FADD at P-Ser194-Pro195.