Tomassini Barbara, Malisan Florence, Franchi Luigi, Nicolò Chiara, Calvo Gloria Brea, Saito Takashi, Testi Roberto
Laboratory of Immunology and Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
FASEB J. 2004 Oct;18(13):1553-5. doi: 10.1096/fj.04-1675fje. Epub 2004 Aug 19.
An accelerated activity of the GD3 synthase (ST8), with consequent GD3 accumulation, is part of the response to environmental stressors in different cell types. Depending on specific, yet largely undefined, cellular settings, this can be followed by adaptation or apoptosis, the latter mostly due to GD3-induced mitochondrial damage. Here we show that subcellular localization of ST8 could significantly affect the biological outcome of GD3 accumulation. Binding to the molecular chaperone calnexin causes the retention of ST8 within the endoplasmic reticulum (ER) and prevents its relocalization to the Golgi. Calnexin-dependent ER retention does not affect the activity of ST8; yet the de novo synthesized GD3 largely fails to reach the mitochondria. Accordingly, overexpression of calnexin suppresses the pro-apoptotic activity of ST8, while the loss of calnexin sensitizes the cells to ST8-induced apoptosis. Reconstitution of calnexin confers protection to deficient cells. Thus, calnexin controls the biological outcome of GD3 accumulation and reveals a novel role in the stress response.
GD3合成酶（ST8）活性的加速以及随之而来的GD3积累，是不同细胞类型对环境应激源反应的一部分。根据特定但很大程度上未明确的细胞环境，这可能随后伴随着适应或凋亡，后者主要是由于GD3诱导的线粒体损伤。在这里，我们表明ST8的亚细胞定位可显著影响GD3积累的生物学结果。与分子伴侣钙连蛋白结合会导致ST8滞留在内质网（ER）内，并阻止其重新定位到高尔基体。钙连蛋白依赖性的内质网滞留不影响ST8的活性；然而，新合成的GD3大多无法到达线粒体。因此，钙连蛋白的过表达抑制了ST8的促凋亡活性，而钙连蛋白的缺失使细胞对ST8诱导的凋亡敏感。钙连蛋白的重建赋予对缺陷细胞的保护作用。因此，钙连蛋白控制着GD3积累的生物学结果，并揭示了其在应激反应中的新作用。
