Livin promotes Smac/DIABLO degradation by ubiquitin–proteasome pathway

Abstract

Livin, a member of the inhibitor of apoptosis protein (IAP) family, encodes a protein containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. It has been reported that Livin directly interacts with caspase-3 and -7 in vitro and caspase-9 in vivo via its BIR domain and is negatively regulated by Smac/DIABLO. Nonetheless, the detailed mechanism underlying its antiapoptotic function has not yet been fully characterized. In this report, we provide, for the first time, the evidence that Livin can act as an E3 ubiquitin ligase for targeting the degradation of Smac/ DIABLO. Both BIR domain and RING finger domain of Livin are required for this degradation in vitro and in vivo. We also demonstrate that Livin is an unstable protein with a half-life of less than 4 h in living cells. The RING domain of Livin promotes its auto-ubiquitination, whereas the BIR domain is likely to display degradation-inhibitory activity. Mutation in the Livin BIR domain greatly enhances its instability and nullifies its binding to Smac/DIABLO, resulting in a reduced antiapoptosis inhibition. Our findings provide a novel function of Livin: it exhibits E3 ubiquitin ligase activity to degrade the pivotal apoptotic regulator Smac/DIABLO through the ubiquitin-proteasome pathway.

Challenge and promise: roles for Livin in progression and therapy of cancer

“…In XIAP, c-IAP1, and c-IAP2, the most prominent roles of RING domains have been shown to encode ubiquitin protease ligase activity, which is preceded by ubiquitinactivating enzymes and ubiquitin-conjugating enzymes in the cascade of protein ubiquitination, and then to catalyze the transfer of ubiquitin into target proteins (16). A similar function of the RING domain has also been detected in Livin, and some studies reveal that it may play an additional role in the subcellular distribution directing apoptosis (17).…”

Characterisation of the anti-apoptotic function of survivin-ΔEx3 during TNFα−mediated cell death

“…Some members of the IAP family are E3 ubiquitin ligases (Vaux and Silke, 2005), involved in substrate ubiquitination and degradation by the 26S proteasome. For example, XIAP and livin protect cells from TRAIL-induced apoptosis by targeting proapoptotic molecules, such as Smac/DIABLO, for proteasomal degradation (MacFarlane et al, 2002;Ma et al, 2006). It remains to be investigated whether survivin-DEx3 holds ubiquitin-ligase activity, or interacts with an E3 ligase to protect cells from mitochondrial damage by targeting pro-apoptotic molecules for proteasomal degradation.…”

Effect of RNAi-mediated silencing of Livin gene on biological properties of colon cancer cell line LoVo

“…Livin is an important member of IAPs, and the anti-apoptotic activity of Livin is mediated through the inhibition of caspase-3, -7, and -9, as well as by its E3 ubiquitin-ligase-like activity, which promotes the degradation of all IAPs (Ma et al, 2006;Chang and Schimmer, 2007). Livin can inhibit initiator caspase-9, but caspase-9 and -8 cannot cleave Livin.…”