Sci. STKE, 27 June 2000
Immunology TRAIL Take the Fas Track
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is thought to regulate cell death events in the immune system through DR4 and DR5, members of the TNF receptor superfamily. Like other death receptors including Fas and TNFR, DR4 and DR5 have death domains in their cytoplasmic tails that recruit proteins to initiate a cell death signaling cascade. However, unlike Fas and TNFR, the mechanism by which DR4 and DR5 elicit apoptosis has not been clear. Sprick et al. and Kischel et al. attribute the confusion to studies based on overexpression of proteins. The two groups analyzed endogenous receptors and signaling protein in B and T cell lines and report that DR4 and DR5 recruit a death-inducing signaling complex that includes the adaptor molecules FADD and caspase-8, molecules utilized by both Fas and TNFR. However, DR4 and DR5 do not utilize the adaptors TRADD or RIP, which are also used by TNFR. Sprick et al. show that cells deficient in FADD or caspase-8 were resistant to TRAIL-induced apoptosis. Kischel et al. also clarify that TRAIL/Apo2L causes DR4 and DR5 to form heteromeric complexes and both groups demonstrate that hetero- and homomeric receptor complexes use the same signaling mechanism. Hence, the physiological conditions used in these studies indicate that DR4 and DR5 operate most similarly to Fas.
Sprick, M.R., Weigand, M.A., Rieser, E., Rauch, C.T., Juo, P., Blenis, J., Krammer, P.H., and Walczak, H. (2000) FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12: 599-609. [Online Journal]
Kischel, F.C., Lawrence, D.A., Chuntharapai, A., Schow, P., Kim, K.J., and Ashkenazi, A. (2000) Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12: 611-620. [Online Journal]
Citation: TRAIL Take the Fas Track. Sci. STKE 2000, tw9 (2000).
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