Pin1-FADD interactions regulate fas-mediated apoptosis in activated eosinophils

Jiyoung Oh, James S. Malter

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Abnormally long-lived eosinophils (Eos) are the major inflammatory component of allergic responses in the lungs of active asthmatics. Eos recruited to the airways after allergen exposure produce and respond to IL-5 and GM-CSF, enhancing their survival. Prosurvival signaling activates Pin1, a peptidyl-prolyl cis-trans isomerase that binds to Bax and prevents its activation. How longlived Eos, despite the continued presence of GM-CSF or IL-5, eventually undergo apoptosis to end allergic inflammation remains unclear. In this study, we show that Pin1 location, activity, and protein interactions are jointly influenced by Fas and the prosurvival cytokine IL-5. Fas signaling strongly induced the phosphorylation of FADD at Ser194 and Pin1 at Ser16, as well as their nuclear accumulation. Phospho-mimic Ser194Glu FADD mutants accelerated Eos apoptosis compared with wild-type or Ser 194Ala mutants. Downstream of FADD phosphorylation, caspase 8, 9, and 3 cleavage, as well as Eos apoptosis induced by Fas, were reduced by constitutively active Pin1 and enhanced by Pin1 inhibition. Pin1 was activated by IL-5, whereas simultaneous IL-5 and anti-Fas treatment modestly reduced peptidyl isomerase activity but induced Pin1 to associate with FADD after its phosphorylation at Ser194. Mechanistically, Pin1-mediated isomerization facilitated the subsequent dephosphorylation of Ser194 FADD and maintenance of cytoplasmic location. In vivo-activated bronchoalveolar Eos obtained after allergen challenge showed elevated survival and Pin1 activity that could be reversed by anti-Fas. Therefore, our data suggest that Pin1 is a critical link between FADD-mediated cell death and IL-5-mediated prosurvival signaling.

Original languageEnglish (US)
Pages (from-to)4937-4945
Number of pages9
JournalJournal of Immunology
Volume190
Issue number10
DOIs
StatePublished - May 15 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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