ORIGINAL ARTICLE

Cell Research (2008): 900-910
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GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth

Bicheng Zhang^1,*, Jun Huang^2,*, Hong-Liang Li^3,*, Ting Liu², Yan-Yi Wang⁴, Paul Waterman¹, Ai-Ping Mao⁴, Liang-Guo Xu¹, Zhonghe Zhai², Depei Liu^3,§, Philippa Marrack^1,§ and Hong-Bing Shu^4,§

Correspondence: Hong-Bing Shu Tel/Fax: +86-27-68753780 E-mail: shuh@whu.edu.cn *These three authors contributed equally to this work. §These three authors are co-corresponding authors.

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Here, we report the identification of GIDE, a mitochondrially located E3 ubiquitin ligase. GIDE contains a C-terminal RING finger domain, which is mostly conserved with those of the IAP family members and is required for GIDE's E3 ligase activity. Overexpression of GIDE induces apoptosis via a pathway involving activation of caspases, since caspase inhibitors, XIAP and an inactive mutant of caspase-9 block GIDE-induced apoptosis. GIDE also activates JNK, and blockage of JNK activation inhibits GIDE-induced release of cytochrome c and Smac as well as apoptosis, suggesting that JNK activation precedes release of cytochrome c and Smac and is required for GIDE-induced apoptosis. These pro-apoptotic properties of GIDE require its E3 ligase activity. When somewhat over- or underexpressed, GIDE slows or accelerates cell growth, respectively. These pro-apoptotic or growth inhibition effects of GIDE may account for its absence in tumor cells.

Cell Research (2008) 18:900–910. doi: 10.1038/cr.2008.75; published online 1 July 2008

Keywords: GIDE, apoptosis, E3 ligase, mitochondria, caspase, JNK