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MBC in Press, published online ahead of print September 8, 2004
Mol. Biol. Cell 10.1091/mbc.E04-03-0184

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Submitted on March 5, 2004
Revised on August 17, 2004
Accepted on August 27, 2004

Differential Regulation of the TRAIL Death Receptors DR4 and DR5 by the Signal Recognition Particle

Yan-Guo Ren,* Klaus W. Wagner,*{dagger} Deborah A. Knee,{ddagger} Pedro Aza-Blanc,{sect} Marc Nasoff,{ddagger} and Quinn L. Deveraux*||

*Department of Cancer Biology, {ddagger}Department of Protein Sciences, {sect}Department of Genomics, Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121

Monitoring Editor: Keith Yamamoto

TRAIL (TNF-Related Apoptosis-Inducing Ligand) death receptors DR4 and DR5 facilitate the selective elimination of malignant cells through the induction of apoptosis. From previous studies the regulation of the DR4 and DR5 cell-death pathways appeared similar; nevertheless, in this study we screened a library of small interfering RNA (siRNA) for genes, which when silenced, differentially affect DR4 vs. DR5-mediated apoptosis. These experiments revealed that expression of the signal recognition particle (SRP) complex is essential for apoptosis mediated by DR4, but not DR5. Selective diminution of SRP subunits by RNA interference resulted in a dramatic decrease in cell surface DR4 receptors that correlated with inhibition of DR4-dependent cell-death. Conversely, SRP silencing had little influence on cell surface DR5 levels or DR5-mediated apoptosis. Although loss of SRP function in bacteria, yeast, and protozoan parasites causes lethality or severe growth defects, we observed no overt phenotypes in the human cancer cells studied--even in stable cell lines with diminished expression of SRP components. The lack of severe phenotype following SRP-depletion allowed us to delineate for the first time, a mechanism for the differential regulation of the TRAIL death receptors DR4 and DR5--implicating the SRP complex as an essential component of the DR4 cell-death pathway.

{dagger}Current address: Department of Molecular Diagnostics,Genentech,1 DNA Way, South San Francisco, CA 94080.

||Corresponding author. E-mail: deveraux{at}gnf.org




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