Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment Academic Article uri icon

abstract

  • A role for cellular inhibitors of apoptosis (IAPs [cIAPs]) in preventing CD95 death has been suspected but not previously explained mechanistically. In this study, we find that the loss of cIAPs leads to a dramatic sensitization to CD95 ligand (CD95L) killing. Surprisingly, this form of cell death can only be blocked by a combination of RIP1 (receptor-interacting protein 1) kinase and caspase inhibitors. Consistently, we detect a large increase in RIP1 levels in the CD95 death-inducing signaling complex (DISC) and in a secondary cytoplasmic complex (complex II) in the presence of IAP antagonists and loss of RIP1-protected cells from CD95L/IAP antagonist-induced death. Cells resistant to CD95L/IAP antagonist treatment could be sensitized by short hairpin RNA-mediated knockdown of cellular FLICE-inhibitory protein (cFLIP). However, only cFLIP(L) and not cFLIP(S) interfered with RIP1 recruitment to the DISC and complex II and protected cells from death. These results demonstrate a fundamental role for RIP1 in CD95 signaling and provide support for a physiological role of caspase-independent death receptor-mediated cell death.

authors

  • Geserick, Peter
  • Hupe, Mike
  • Moulin, Maryline
  • Wong, W Wei-Lynn
  • Feoktistova, Maria
  • Kellert, Beate
  • Gollnick, Harald
  • Silke, John
  • Leverkus, Martin

publication date

  • December 28, 2009

has subject area