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Molecular and Cellular Biology, October 2006, p. 7046-7055, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00520-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Differential Inhibition of TRAIL-Mediated DR5-DISC Formation by Decoy Receptors 1 and 2

INSERM, U517, Université de Bourgogne, Dijon F-21000, France,¹ Biochemistry Department, University of Lausanne, Boveresses 155, CH-1066 Epalinges, Switzerland²

Received 24 March 2006/ Returned for modification 4 May 2006/ Accepted 17 July 2006

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that induces cancer cell death by apoptosis with some selectivity. TRAIL-induced apoptosis is mediated by the transmembrane receptors death receptor 4 (DR4) (also known as TRAIL-R1) and DR5 (TRAIL-R2). TRAIL can also bind decoy receptor 1 (DcR1) (TRAIL-R3) and DcR2 (TRAIL-R4) that fail to induce apoptosis since they lack and have a truncated cytoplasmic death domain, respectively. In addition, DcR1 and DcR2 inhibit DR4- and DR5-mediated, TRAIL-induced apoptosis and we demonstrate here that this occurs through distinct mechanisms. While DcR1 prevents the assembly of the death-inducing signaling complex (DISC) by titrating TRAIL within lipid rafts, DcR2 is corecruited with DR5 within the DISC, where it inhibits initiator caspase activation. In addition, DcR2 prevents DR4 recruitment within the DR5 DISC. The specificity of DcR1- and DcR2-mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling.

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