XIAP binds TLE

XIAP (X-linked inhibitor of apoptosis) has three BIR domains with known roles in the degradation of caspases and a C-terminal E3 ligase domain with both anti-apoptotic and non-apoptotic roles (Galban and Duckett, 2010; Burstein et al, 2004). The Drosophila homologue DAIP1 was recently identified in a screen in S2 cells for regulators of Wg signalling (Hanson et al, 2012). Knockdown of XIAP in HEK293 cells reduces WNT3a-induced reporter activity and expression of endogenous WNT target genes without affecting beta-catenin levels or localization. In vitro studies show that XIAP can ubiquitinate all human TLE isoforms, including the truncated isoform Amino-terminal enhancer of split (AES). TLE3 co-immunoprecipitates with XIAP from HEK293 cells in both the presence and absence of WNT signalling, consistent with a constitutive role for XIAP in TLE regulation. XIAP may act either by ubiquitinating free nuclear TLE to reduce the amount available to interact with TCF/LEFs or by ubiquitinating TLE in the context of TCF/LEF transcriptional complexes to promote its dissociation, or both. In support of the latter model, XIAP is pulled down with TCF7L2 (TCF4) in a WNT-dependent manner, and knockdown of XIAP reduces the amount of beta-catenin that co-immunoprecipitates with TCF7L2 (TCF4) upon WNT pathway activation (Hanson et al, 2012).

XIAP（X连锁的凋亡抑制因子）具有三个已知在caspase降解中发挥作用的BIR结构域，以及一个具有抗凋亡和非凋亡作用的C端E3连接酶结构域（Galban和Duckett，2010；Burstein等，2004）。果蝇同源物DAIP1最近在S2细胞中进行的Wg信号通路调节因子筛选中被鉴定出（Hanson等，2012）。在HEK293细胞中敲低XIAP会减少WNT3a诱导的报告基因活性和内源WNT靶基因的表达，而不影响β-连环蛋白的水平或定位。体外研究表明，XIAP可以泛素化所有人类TLE异构体，包括截断异构体氨基末端分裂增强子（AES）。TLE3在与HEK293细胞共免疫沉淀时，无论是在WNT信号通路的激活与否，都与XIAP共沉淀，这表明XIAP在TLE调节中发挥构成性作用。XIAP可能通过泛素化游离的核TLE以减少其与TCF/LEFs相互作用的量，或者通过泛素化TCF/LEF转录复合物中的TLE以促进其解离，或者两者兼而有之。支持后一种模型的是，XIAP以WNT依赖的方式与TCF7L2（TCF4）共沉淀，而敲低XIAP会减少WNT通路激活后与TCF7L2（TCF4）共沉淀的β-连环蛋白量（Hanson等，2012）。