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DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD.

DJ-1 was initially identified as an oncogene product involved in human tumorigenesis in cooperation with Ras. Increased DJ-1 expression is associated with tumorigenesis in many cancers, whereas the loss of DJ-1 function is linked to an autosomal recessive form of Parkinson's disease (PD). It has been reported that DJ-1 protects cells from TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. However, the mechanism by which DJ-1 is involved is still largely unknown. Here we show that DJ-1 inhibits TRAIL-induced apoptosis by blocking Fas-associated protein death domain (FADD)-mediated pro-caspase-8 activation. Wild-type DJ-1, but not the PD-associated mutant L166P, binds to FADD to inhibit the formation of the death-inducing signaling complex (DISC). DJ-1 competes with pro-caspase-8 to bind to FADD at the death effector domain, thereby repressing the recruitment and activation of pro-caspase-8 to the active form of caspase-8. Thus, our study suggests that DJ-1 protects against TRAIL-induced apoptosis through the regulation of DISC formation.

Pubmed ID: 21785459

Authors

  • Fu K
  • Ren H
  • Wang Y
  • Fei E
  • Wang H
  • Wang G

Journal

Oncogene

Publication Data

March 8, 2012

Associated Grants

None

Mesh Terms

  • Apoptosis
  • Caspase 8
  • Caspase Inhibitors
  • Cells, Cultured
  • Fas-Associated Death Domain Protein
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • Protein Transport
  • RNA, Messenger
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Suppressor Protein p53