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J. Biol. Chem., Vol. 281, Issue 16, 11235-11249, April 21, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/16/11235    most recent M508779200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by He, L. Articles by Lipsky, P. E. Search for Related Content PubMed PubMed Citation Articles by He, L. Articles by Lipsky, P. E. Social Bookmarking                      What's this?

TRAF6 Regulates Cell Fate Decisions by Inducing Caspase 8-dependent Apoptosis and the Activation of NF-B^*

Liusheng He¹, Xiaoli Wu, Richard Siegel, and Peter E. Lipsky

From the Flow Cytometry Section, Office of Science and Technology and the Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892

Tumor necrosis factor receptor-associated factor 6 (TRAF6) functions as an adaptor, positively regulating the NF-B pathway. Here we report a new function of human TRAF6, the direct stimulation of apoptosis. The mechanism of apoptosis induction results from the capacity of human TRAF6 to interact and activate caspase 8. Both the C-terminal TRAF domain of human TRAF6, which directly interacts with the death effector domain of pro-caspase 8, and the N-terminal RING domain, which is required for activation of caspase 8, are necessary for the induction of apoptosis. The role of endogenous TRAF6 in regulating apoptosis was confirmed by extinguishing TRAF6 expression with specific small-hairpin RNA that resulted in diminished spontaneous apoptosis and resistance to induced apoptosis. In contrast to the human molecule, murine TRAF6 displayed less ability to induce apoptosis and a greater capacity to stimulate NF-B activity. Human and murine TRAF6 are similar except in the region between zinc finger 5 and the TRAF domains. Reciprocal transfer of this connecting region completely exchanged the ability of human and murine TRAF6 to induce apoptosis and activate NF-B. Unique regions of TRAF6 therefore play an important role in determining cell fate.

Received for publication, August 9, 2005 , and in revised form, January 10, 2006.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and supplemental Fig. 1.

¹ To whom correspondence should be addressed. E-mail: Liusheng.He{at}Stjude.org.

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