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J. Biol. Chem., Vol. 279, Issue 6, 4313-4321, February 6, 2004

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Unlike Diablo/smac, Grim Promotes Global Ubiquitination and Specific Degradation of X Chromosome-linked Inhibitor of Apoptosis (XIAP) and Neither Cause Apoptosis^*

John Silke, Tobias Kratina, Paul G. Ekert¶||, Miha Pakusch, and David L. Vaux**

From the Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, VIC 3050, Australia and the ^¶Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Parkville 3052, Australia

Grim is a Drosophila inhibitor of apoptosis (IAP) antagonist that directly interferes with inhibition of caspases by IAPs. Expression of Grim, or removal of DIAP1, is sufficient to activate apoptosis in fly cells. Transient expression of Grim in mammalian cells induces apoptosis, arguing for the conservation of apoptotic pathways, but cytoplasmic expression of the mammalian IAP antagonist Diablo/smac does not. To understand why, we compared Grim and Diablo. Although they have the same IAP binding specificity, only Grim promoted XIAP ubiquitination and degradation. Grim also synergized with XIAP to promote an increase in total cellular ubiquitination, whereas Diablo antagonized this activity. Surprisingly, Grim-induced ubiquitination of XIAP did not require the IAP RING finger. Analysis of a Grim mutant that promoted XIAP degradation, but was not cytotoxic, suggests that Grim killing in transient assays is due to a combination of IAP depletion, blocking of IAP-mediated caspase inhibition, and at least one other unidentified function. Unlike transiently transfected cells, inducible mammalian cell lines can sustain continuous expression of Grim and selective degradation of XIAP without undergoing apoptosis, demonstrating that down-regulation and antagonism of IAPs is not sufficient to cause apoptosis of mammalian cells.

Received for publication, May 30, 2003 , and in revised form, October 20, 2003.

^* This work was supported by the NHMRC 257502. 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.

^|| Funded by an NHMRC career development grant.

^** A Scholar of the Leukemia and Lymphoma Society.

To whom correspondence should be addressed. Tel.: 61-3-9345-2548; Fax: 61-3-9347-0852; E-mail: silke{at}wehi.edu.au.

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