Zhao Guoping, Lu Huayi, Li Chi
From the Molecular Targets Program, Departments of Medicine, Pharmacology, and Toxicology, University of Louisville, Louisville, Kentucky 40202 and.
the Second Hospital, Jilin University, Changchun, Jilin Province, China 130041.
J Biol Chem. 2015 Apr 3;290(14):8949-63. doi: 10.1074/jbc.M114.619353. Epub 2015 Feb 19.
Protein disulfide isomerase (PDI) family proteins are classified as enzymatic chaperones for reconstructing misfolded proteins. Previous studies have shown that several PDI members possess potential proapoptotic functions. However, the detailed molecular mechanisms of PDI-mediated apoptosis are not completely known. In this study, we investigated how two members of PDI family, PDI and PDIA3, modulate apoptotic signaling. Inhibiting PDI and PDIA3 activities pharmacologically alleviates apoptosis induced by various apoptotic stimuli. Although a decrease of PDIA3 expression alleviates apoptotic responses, overexpression of PDIA3 exacerbates apoptotic signaling. Importantly, Bak, but not Bax, is essential for PDIA3-induced proapoptotic signaling. Furthermore, both purified PDI and PDIA3 proteins induce Bak-dependent, but not Bax-dependent, mitochondrial outer membrane permeabilization in vitro, probably through triggering Bak oligomerization on mitochondria. Our results suggest that both of PDI and PDIA3 possess Bak-dependent proapoptotic function through inducing mitochondrial outer membrane permeabilization, which provides a new mechanism linking ER chaperone proteins and apoptotic signaling.
蛋白质二硫键异构酶（PDI）家族蛋白被归类为用于重构错误折叠蛋白的酶伴侣。先前的研究表明，几个PDI成员具有潜在的促凋亡功能。然而，PDI介导的凋亡的详细分子机制尚不完全清楚。在本研究中，我们研究了PDI家族的两个成员PDI和PDIA3如何调节凋亡信号。药理学上抑制PDI和PDIA3的活性可减轻由各种凋亡刺激诱导的凋亡。虽然PDIA3表达的降低减轻了凋亡反应，但PDIA3的过表达加剧了凋亡信号。重要的是，Bak而非Bax对于PDIA3诱导的促凋亡信号至关重要。此外，纯化的PDI和PDIA3蛋白在体外均诱导依赖于Bak而非依赖于Bax的线粒体外膜通透性改变，可能是通过触发Bak在线粒体上的寡聚化。我们的结果表明，PDI和PDIA3均通过诱导线粒体外膜通透性改变而具有依赖于Bak的促凋亡功能，这提供了一种将内质网伴侣蛋白与凋亡信号联系起来的新机制。
