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Originally published as MBC in Press, 10.1091/mbc.E04-12-1051 on May 25, 2005

Vol. 16, Issue 8, 3521-3528, August 2005

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Trypanosoma cruzi Posttranscriptionally Up-Regulates and Exploits Cellular FLIP for Inhibition of Death-inducing Signal

Muneaki Hashimoto, Junko Nakajima-Shimada, and Takashi Aoki

Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan

Submitted December 3, 2004; Revised May 10, 2005; Accepted May 18, 2005
Monitoring Editor: Donald Newmeyer

Intracellular persistence of the protozoan parasite, Trypanosoma cruzi, is an aggravating cause of Chagas' disease, involving that the protozoan infection specifically inhibits death receptor-mediated apoptosis of host cells. Here we demonstrate that the parasite dramatically up-regulates cellular FLICE inhibitory protein (c-FLIP), the only known mammalian inhibitor specific for death receptor signaling, in infected cells by an unusual, posttranscriptional stabilization of the short-lived protein. We also show that c-FLIP is accumulated in T. cruzi–infected mouse heart muscle cells in vivo. Stimulation of death receptor Fas in infected cells induces recruitment of c-FLIP to block the procaspase-8 activation at the most upstream caspase cascade. c-FLIP knock-down with a small interfering RNA significantly restores Fas-mediated apoptosis in infected cells. Taken together, our findings indicate that T. cruzi posttranscriptionally up-regulates and exploits host c-FLIP for the inhibition of death-inducing signal, a mechanism that may allow parasites to persist in host cells.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E04–12–1051) on May 25, 2005.

Abbreviations used: c-FLIP, cellular FLICE inhibitory protein; c-FLIPL, c-FLIP long; DISC, death-inducing signaling complex; FADD, Fas-associated death domain-containing protein; siRNA, small interfering RNA oligoribonucleotide.

Address correspondence to: Takashi Aoki (tksaoki{at}med.juntendo.ac.jp).






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