Death Receptor Signaling

Apoptosis can be induced through the activation of death receptors including Fas, TNFαR, DR3, DR4, and DR5 by their respective ligands. Death receptor ligands characteristically initiate signaling via receptor oligomerization, which in turn results in the recruitment of specialized adaptor proteins and activation of caspase cascades. Binding of FasL induces Fas trimerization, which recruits initiator caspase-8 via the adaptor protein FADD. Caspase-8 then oligomerizes and is activated via autocatalysis. Activated caspase-8 stimulates apoptosis via two parallel cascades: it can directly cleave and activate caspase-3, or alternatively, it can cleave Bid, a pro-apoptotic Bcl-2 family protein. Truncated Bid (tBid) translocates to mitochondria, inducing cytochrome c release, which sequentially activates caspase-9 and -3. TNF-α and DR-3L can deliver pro- or anti-apoptotic signals. TNFαR and DR3 promote apoptosis via the adaptor proteins TRADD/FADD and the activation of caspase-8. Interaction of TNF-α with TNFαR may activate the NF-κB pathway via NIK/IKK. The activation of NF-κB induces the expression of pro-survival genes including Bcl-2 and FLIP, the latter can directly inhibit the activation of caspase-8. FasL and TNF-α may also activate JNK via ASK1/MKK7. Activation of JNK may lead to the inhibition of Bcl-2 by phosphorylation. In the absence of caspase activation, stimulation of death receptors can lead to the activation of an alternative programmed cell death pathway termed necroptosis by forming complex IIb.

Selected Reviews:

• Declercq W, Vanden Berghe T, Vandenabeele P (2009) RIP kinases at the crossroads of cell death and survival. Cell 138(2), 229–32.
• Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147(4), 742–58.
• Kantari C, Walczak H (2011) Caspase-8 and bid: caught in the act between death receptors and mitochondria. Biochim. Biophys. Acta 1813(4), 558–63.
• Kaufmann T, Strasser A, Jost PJ (2012) Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ. 19(1), 42–50.
• Lavrik IN, Krammer PH (2012) Regulation of CD95/Fas signaling at the DISC. Cell Death Differ. 19(1), 36–41.
• Van Herreweghe F, Festjens N, Declercq W, Vandenabeele P (2010) Tumor necrosis factor-mediated cell death: to break or to burst, that's the question. Cell. Mol. Life Sci. 67(10), 1567–79.
• Wajant H, Scheurich P (2011) TNFR1-induced activation of the classical NF-κB pathway. FEBS J. 278(6), 862–76.

We would like to thank Prof. Junying Yuan, Harvard Medical School, Boston, MA, for reviewing this diagram.

created September 2008

revised September 2016