TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins
TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins
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DOI：
10.1038/cdd.2011.128
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发表时间：
2012-04-01
影响因子：
12.4
通讯作者：
Esposito, F.
中科院分区：
文献类型：
--
作者：
Amoroso, M. R.;Matassa, D. S.;Esposito, F.
肿瘤坏死因子受体相关蛋白-1（TRAP 1）是一种线粒体（MITO）抗凋亡热休克蛋白。关于TRAP 1通路的可用信息描述了该蛋白在线粒体中的一些良好表征的功能。然而，我们的小组的质谱分析的使用确定TBP 7，AAA-ATP酶的19 S蛋白酶体亚基，作为一个假定的TRAP 1相互作用蛋白。令人惊讶的是，TRAP 1和TBP 7共定位在内质网（ER），如生化和共聚焦/电子显微镜分析所示，并直接相互作用，如荧光共振能量转移分析所证实的。这是首次证明TRAP 1存在于该细胞区室中。在暴露于毒胡萝卜素诱导的ER应激的细胞中，TRAP 1通过短发夹RNA沉默与BiP/Grp 78的上调相关，从而表明TRAP 1在受损蛋白的重折叠和ER应激保护中的作用。一致地，TRAP 1和/或TBP 7干扰增强应激诱导的细胞死亡和增加细胞内蛋白泛素化。这些实验使我们假设TRAP 1通过与调节性蛋白酶体蛋白TBP 7相互作用参与错误定位/错误折叠的目的蛋白质的蛋白质质量控制。值得注意的是，特定的MITO蛋白的表达下降后TRAP 1干扰增加的泛素化的结果。所提出的TRAP 1网络在体内具有影响，因为它在人类结直肠癌中是保守的，由ER定位的TRAP 1与TBP 7相互作用控制，并提供了ER-线粒体串扰的新模型。Cell Death and Differentiation（2012）19，592-604; doi：10.1038/cdd.2011.128; 2011年10月7日在线发表
Tumor necrosis factor receptor-associated protein-1 (TRAP1) is a mitochondrial (MITO) antiapoptotic heat-shock protein. The information available on the TRAP1 pathway describes just a few well-characterized functions of this protein in mitochondria. However, our group's use of mass-spectrometric analysis identified TBP7, an AAA-ATPase of the 19S proteasomal subunit, as a putative TRAP1-interacting protein. Surprisingly, TRAP1 and TBP7 colocalize in the endoplasmic reticulum (ER), as demonstrated by biochemical and confocal/electron microscopic analyses, and interact directly, as confirmed by fluorescence resonance energy transfer analysis. This is the first demonstration of TRAP1's presence in this cellular compartment. TRAP1 silencing by short-hairpin RNAs, in cells exposed to thapsigargin-induced ER stress, correlates with upregulation of BiP/Grp78, thus suggesting a role of TRAP1 in the refolding of damaged proteins and in ER stress protection. Consistently, TRAP1 and/or TBP7 interference enhanced stress-induced cell death and increased intracellular protein ubiquitination. These experiments led us to hypothesize an involvement of TRAP1 in protein quality control for mistargeted/misfolded mitochondria-destined proteins, through interaction with the regulatory proteasome protein TBP7. Remarkably, expression of specific MITO proteins decreased upon TRAP1 interference as a consequence of increased ubiquitination. The proposed TRAP1 network has an impact in vivo, as it is conserved in human colorectal cancers, is controlled by ER-localized TRAP1 interacting with TBP7 and provides a novel model of the ER-mitochondria crosstalk. Cell Death and Differentiation (2012) 19, 592-604; doi:10.1038/cdd.2011.128; published online 7 October 2011