dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8

Cell Death Differ. 2012 Sep;19(9):1482-94. doi: 10.1038/cdd.2012.22. Epub 2012 Mar 16.


Toll-like receptor 3 (TLR3) is a pattern-recognition receptor known to initiate an innate immune response when stimulated by double-stranded RNA (dsRNA). Components of TLR3 signaling, including TIR domain-containing adapter inducing IFN-α (TRIF), have been demonstrated to contribute to dsRNA-induced cell death through caspase-8 and receptor interacting protein (RIP)1 in various human cancer cells. We provide here a detailed analysis of the caspase-8 activating machinery triggered in response to Poly(I:C) dsRNA. Engagement of TLR3 by dsRNA in both type I and type II lung cancer cells induces the formation of an atypical caspase-8-containing complex that is devoid of classical death receptors of the TNFR superfamily, but instead is physically associated to TLR3. The recruitment of caspase-8 to TLR3 requires RIP1, and is negatively modulated by cellular inhibitor of apoptosis protein (cIAP)2-TNF receptor-associated factor (TRAF)2-TNFR-associated death domain (TRADD) ubiquitin ligase complex, which regulates RIP1 ubiquitination. Intriguingly, unlike Fas- or TRAILR-dependent death signaling, caspase-8 recruitment and activation within the TLR3 death-signaling complex appears not to be stringently dependent on Fas-associated with death domain (FADD). Our findings uncover a novel aspect of the molecular mechanisms involved during apoptosis induced by the innate immune receptor TLR3 in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Line, Tumor
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism
  • RNA, Double-Stranded / pharmacology*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TNF Receptor-Associated Death Domain Protein / genetics
  • TNF Receptor-Associated Death Domain Protein / metabolism
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism*
  • Ubiquitin-Protein Ligases
  • Ubiquitination / drug effects
  • Ubiquitination / genetics


  • AGFG1 protein, human
  • Inhibitor of Apoptosis Proteins
  • Nuclear Pore Complex Proteins
  • RNA, Double-Stranded
  • RNA-Binding Proteins
  • TLR3 protein, human
  • TNF Receptor-Associated Death Domain Protein
  • TNF Receptor-Associated Factor 2
  • Toll-Like Receptor 3
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • CASP8 protein, human
  • Caspase 8