Unlike Diablo/smac, Grim promotes global ubiquitination and specific degradation of X chromosome-linked inhibitor of apoptosis (XIAP) and neither cause apoptosis
Details
Publication Year 2004-02-06, Volume 279, Issue #6, Page 4313-4321
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
Publication Type
Journal Article
Abstract
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 LAP antagonist Diablo/smac does not. To understand why, we compared Grim and Diablo. Although they have the same LAP 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 LAP-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.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords
PROTEIN LIGASE ACTIVITY; CELL-DEATH; DROSOPHILA-REAPER; IN-VITRO; DIAP1; HID; CASPASE-3; SURVIVAL; PATHWAY; MORGUE
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Creation Date: 2004-02-06 12:00:00
Last Modified: 0001-01-01 12:00:00
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