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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0803428v1 183/5/3278    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Morgan, M. J. Articles by Liu, Z.-g. PubMed PubMed Citation Articles by Morgan, M. J. Articles by Liu, Z.-g.

Membrane-Bound Fas Ligand Requires RIP1 for Efficient Activation of Caspase-8 within the Death-Inducing Signaling Complex¹

Michael J. Morgan^2,*, You-Sun Kim^*, and Zheng-gang Liu^*

^* Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Institute for Medical Sciences, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, Korea

The serine-threonine kinase RIP1 was originally identified through its ability to bind to the death domain of Fas (CD95). RIP1 has been shown to be recruited to the Fas death-inducing signaling complex (DISC) and is required for the induction of necrotic cell death. In this study, we show that in Jurkat T lymphocytes, RIP1 is also necessary for the most efficient activation of downstream caspases by Fas when treated with membrane-bound Fas ligand, but not with agonistic Abs or cross-linked soluble Fas ligand. RIP1 participates in the Fas-associated death domain protein-mediated recruitment of caspase-8 to the Fas receptor complex in a manner that promotes caspase-8 activation. Cross-linking Abs, such as CH11, bypass the requirement for RIP1 in caspase activation by initiating larger, though less efficient, DISC complexes, while membrane-bound Fas ligand initiates a smaller but more efficient DISC that functions, in part, by effectively incorporating more RIP1 into the complex. Consequently, RIP1 is likely a more integral part of physiological signaling through the Fas/CD95 receptor complex than previously recognized; at least when the signal is mediated by full-length membrane-bound FasL. Cross-linked soluble FasL, which also occurs physiologically, behaves similarly to the CH11 Ab, and may therefore be more likely to initiate nonapoptotic Fas signaling due to less RIP1 in the receptor complex. Thus, agonists that bind the same Fas receptor initiate mechanistically distinct pathways resulting in differential cytotoxicity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of Center for Cancer Research, NCI, National Institutes of Health.

² Address correspondence and reprint requests to Michael Morgan, Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Building 37, Room 1062, 37 Convent Drive, Bethesda, MD 20892. E-mail address: morganmi{at}mail.nih.gov

³ Abbreviations used in this paper: sFasL, soluble portion of FasL; memFasL, membrane-bound Fas ligand; DISC, death-inducing signaling complex. FADD, Fas-associated death domain protein; zVAD, N-Benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone; siRNA, small interferring RNA; MTS, 3-(4,5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.

⁴ The online version of this article contains supplemental material.